>> I'm going to run
the class as follows. I'll have the most
important announcements at the very beginning
of the class. So I'll be talking about
stuff like, what's covered on the midterm, what's expected from your proposal assignment
et cetera at the very beginning. So, you definitely want
to show up on time, show up early get a sit, be prepare because most
important stuff is going to be in that first five minutes. OK. Oh, and by the way,
feel free to interrupt if you have any questions. OK. So, don't hesitate to
interrupt if anything comes up. OK. So some announcements
today, and again, announcements will come out at the very beginning
of each class. Our reading assignments
this week, I like you to obtain a textbook,
it's available on the bookstore, there are big stack of them
when I visited last week. >> They ran out. >> They ran out? Oh, well it's good. OK. If they ran out,
Amazon.com has them on sale and you can get them
delivered very quickly. OK. And I know for while,
Amazon was selling them at some ridiculous discount, so. I know because as one of the
co-authors, I'm very interested in how they're selling. Along those lines, as one of
the co-authors, I'm planning to donate the profits
of the book to anyone in this classroom
back to UCI for-- to support research
in chemistry. OK. So, I'm requiring
a book that I wrote. I'm obviously aware that I'm
going to profit from that. The profits will go
back to UC Irvine. OK. So if you have a
copy of the course reader from previous years,
please throw it away. OK. It's not going
to be any good. I mean it's good, but I've
changed the material quite a bit and the textbook is
significantly improved, the problems are
slightly different. I think it's-- the figures
are much better, et cetera. And of course it was edited. So, the course reader for previous years is
not going to carry you. You need to buy a
copy of the textbook. So, Natalie how does
the sound sound? >> It sounds great
and I'm sorry. Just one quick announcement. I know this is [inaudible]
tiny words could be difficult. So, we can just work on not
having to come back here since I had like 10
minutes to set up. And just go through the
classroom on that side, it would be it would
super helpful [inaudible]. The benefit is though to you that probably [inaudible]
lecture. All of these lectures will
be available in YouTube. >> Cool. >> So, if you can bear with all
my equipment then you can watch these and enjoy them
as many times you want. >> Thank you Nathalie. Yeah. So, yes, they will
be posted online for you. So, you can enjoy them and
study from them et cetera. The goal here is that
you UC Irvine is one of the very first Universities
to have both lecture class and the laboratory class
in chemical biology. We started these back in 2000 when I was an assistant
professor. And since that time, we've
obviously built up quite a bit in terms of our sophistication
of presenting the subject. And so my goal is to
really bring that level to other universities around the
world and around the country. So, any that's why
we're doing this. But it also has some
benefits to you as well. OK. So reading assignment
for the first week. Read Chapter 1. I'm going to be covering all
the material in Chapter 1 so there's nothing for
you to skim through or anything like that. On future chapters,
there will be stuff that I won't be covering and
I'll tell you when that happens. OK. And you'll notice
when it happens. OK. If you want to get a
head, start reading Chapter 2. Chapter 1 is pretty basic. Chapter 2 then starts
getting more advanced. Homework. Do the
problems in Chapter 1, all of the odd problems and also
all of the asterisked problems and let me add that do this. So, all the problems that
have an asterisk are-- the answers to all the problems with an asterisk are
available online. So, I'd like you to
do those as well. OK. And then in addition,
we'll be posting a worksheet, number 1, on the website. It's not there yet but it'll be
posted very-- oh, it is there? >> Well, it'll be
this afternoon. >> It'll be posted afterwards. OK. So, we'll be posting that. That will form the basis
for the discussion sections. Please work the worksheet
as well. OK. So, before I get
started, before I delve through very much more. I want to tell you what
you should be paying attention towards. The first thing are
these announcements that I'm giving you. What's discussed in lecture? The discussions that I give
you in lecture are your guide to what I think it's important. OK. So, right before the
midterm, you're going to want to know, what do I need
to know on the midterm to get an A in this class? And my answer is always
the same which is, what did I talked
about in lecture? What I talk about in lecture
is what I think is important. I have a limited amount of
time for these lectures. I'll be doing two
lectures per chapter of an hour and 20 minutes each. And so, if I talk
about it in lecture, I'm telling you I think
this is important. This is something you need
to know for the midterm. OK. So, what's discussed in
lecture is super important. This includes both slides and
anything else that's posted to the website, discussion
worksheets and then the discussion
in discussion as well. If you're sitting on the
left side of the classroom, can I ask you to sort of scooch in if you have an empty
chair on your right. So, just to create
some more extra chairs because we have people
that are arriving late. So, just sort of
scooch over please. Thank you. OK. The next most important
thing is assigned reading. But filter the assigned
reading through the filter, through the lens of what
I talk about in class. If I talk about it in class
that's telling you it's important, if I don't talked
about it, less important. And then finally, the problems in the textbooks
as least important. Good news, there's a few things that you don't have
to worry about. The first of these are
references on the slides. I find it almost
impossible to do stuff without having some referral
back to the literature. That's sort of the
nature of scholarship and it totally impossible to
get me to stop doing this. When Dave and I wrote the
textbook, for example, we had a list of references
that's like 10 times longer than the one that's
posted to the website. And we found it totally
impossible, the publisher told
us to stop doing it, to leave out those references. And so, references are
basically the currency that underpins what
I'm telling you. But on the other hand, this
is an introductory class. So, don't get worried
about those. OK. If you take a graduate
class and they have references on slides, you'll want to
look up those references. But on an undergraduate level
don't get worked up about it. OK. So, don't stress
about those. In addition, don't stress
about stuff that's covered in the textbook that we
don't discuss in class. OK. So if I, you know,
I've said this before. If I don't discuss
it class and it's in the textbook,
don't worry about it. OK. So, the text
is written as sort of an advanced undergraduate
early graduate level. And there's material there
that's frankly graduate level. But I don't want you to
get stressed out about it. OK. So, if don't talk about
it in class, that's my signal that I don't think it's so
important for you to learn. OK. Any question about
what I'm telling you? Hey. >> Are there any textbooks
reserved in the library? >> That's a good question. What is your name? >> David. >> David. Mariam, could you
look into that for David? >> I know there're not yet
but they are ordering them. So as soon as they got them-- it should be within
the next two weeks. >> OK. So, they'll be-- eventually they'll
appear there but not yet. >> Thank you >> OK. Thanks for asking. Other question? What is your name? [ Inaudible Remark ] No, so we will not be
collecting the problem sets. We'll have plenty of
other chances to learn about your intelligence
and creativity. So another question? >> Will the slides be
posted ahead of time or-- >> Slides will be posted--
that's a good question. I'll try. But I'm usually
frantically getting ready the day. So I'll do my best. Certainly the Thursday
lecture will be. But maybe not the Tuesday. I'll do my very best though. Other questions? OK. More background. Course instructors,
I'm Professor Weiss. I've been teaching this
class for about 12 years. And I absolutely love
chemical biology. It's what makes me run to work. It is my sole passion in life. That's a little bit of an
exaggeration, but close. OK. So what else would
you like to know about me? Here's your chance. For the next five minutes you
can ask anything you want, personal, not so personal. Go ahead in the back first. So, my laboratory
is at the interface of chemistry and biology. And we're trying to
develop new ways of looking at individual molecules and dissecting how
membrane proteins work. Thanks for asking. And a question over here? [ Inaudible Remark ] It was. I'm kind of
a competitive guy. I like driving fast
I like racing. So, yeah. Question over here? >> What's difference
between biochemistry and chemical biology? >> Chemical biology emphasize--
so, this is a great questions. So, the question was
what is the difference between biochemistry
and chemical biology? Chemical biology
emphasizes what's happening at the level of atoms and bonds. And biochemistry
emphasizes what's happening at a larger scale. So, in biochemistry, my
colleagues are content to look at proteins as sort
of large molecules without getting too worked
up about hydrogen bond here and hydrogen bond there. Sometimes they get worked
up about those things. But most of the time,
the diagram-- signal transduction
diagrams and things like that are just large blobs. And in this class, we'll
be zooming in and looking at the actual atoms and bonds. OK, good question. OK. Anything else personal? This is your last chance,
ask me anything personal. Ask me about my pets, my
hobbies, oh, go ahead. [ Inaudible Remak ] No, I wish I did. I only get to go
out once a year. It's kind of the limitation. So thanks for asking. OK. Well, I should also let
you know I have two cats. I'm married and that's it
for the personal information. OK. OK. Last question, go ahead. >> How many kids you have? >> I have zero kids. That's why I have
a two-sitter car. [ Laughter ] OK. You guys, that's it on the
personal stuff, enough about me. I'm very pleased
that this quarter, we have really the very best
TAs in the chemistry department. I've gone through and
I've handpicked TAs, Mariam Ifftikhar is
a great examplist. Mariam and I taught
this class last year and she knows everything there
is to know about this topic. Her research is in
chemical biology and she's absolutely superb. If she tells you something
about the class, you could take that as good as coming from me. OK. In addition, our second TA,
Krithika Mohan isn't here today. She's been tied up in India. But she'll be back in
the next week or so. And she's also a great
source of information. She's also a graduate
student in my laboratory. OK. So, we're lucky to have
California's finest natural resource TAing for us,
Krithika and Mariam. OK. So, in terms
of office hours, I will be having two
office hours a week, my Thursday office hours is set. My Wednesday office hour,
however, will float. OK. So, I will always have
office hours Thursday, 11 to noon. This other office hour, the
second office hour will float, meaning that my schedule
is constantly changing. And so I'll have to
change this around. OK. So, every week,
I will announce when that office
hour will take place. If for example, my office
hours don't fit your schedule, tell me at the beginning
of the week when you like my officer hour to be. And I'll do my best to
accommodate as many people as possibly each week. OK. So, first office hour fixed,
second office hour floating. I will always have the office
hours set up in away that's at the interfaces
between classes. So, you don't have to attend
the whole office hour, if you can attend just the first
15 minutes or so or 10 minutes and then fly off to your
class, that's perfectly OK. Show up for five minutes,
get your question answered and then disappear, I
don't care, I don't mind. But I'll always set them up so
they're kind of at the junction between classes that way
then it's less likely that you'll be able to tell
me that you have a schedule in conflict with everyone
in my office hours. I've heard that before and
I usually ask those people to show me their
schedule classes. And I've never seen
it actually that way, especially since I've the
second office hour floating. So there's going to
be plenty of time for you to meet this quarter. And in fact I really
want to get to know you. OK. I will get to know the names of 95 percent of
you in this room. I will know something about what
your career aspirations are. I will know something about
your creativity in terms of your ability to come
up with noble ideas, your writing ability, and a lot
of other characteristic as well. So, at the end of
this, I will be able to write a very good letter
of recommendation for you. OK. This is not [inaudible] the
last topic, but I would like you to shutoff your cellphones
please. OK. And that also includes
text messaging as well. Thank you. OK. So anyway, come out to
my office hours especially in the first couple of
weeks, introduce yourself. Tell me why it is
you're taking this class. What it is you hope you learn? What it is that you're hoping to do once you graduate
from UC Irvine. And if there's anything
I can do to help you in that course, I will do it. OK. That's one of my jobs. And furthermore, even after
you graduate from this class, you can still keep
in touch with me. You can still get letters
of recommendation from me and you could still
have my support in your career aspirations. OK. That's my promise
and commitment to you. OK. And the TAs will also
have office hours each week. Their office hours were
always be on different days and times than my office hour. And their office hours are much
more fixed than my office hour. OK. So, any questions about
anything I've said any of the announcements so far? OK. All right. Textbook, I've already
mentioned this. Again, it's available on Amazon. I understand it's sold out. But you can get it
again from Amazon. Supplemental text, I'd like you to have available an organic
chemistry supplemental text. When I talk about
peptides, for example, and I talk about amide
bonds, I'm going to assume that you've read the chapter
on amide bonds and peptides in this supplemental text, even
if it wasn't covered in 51C. OK. I'll just ask you to go
back and read that chapter. OK. And so you need some sort
of supplemental text available in organic chemistry as
basically as reference. OK. And it's nice because
this will provide kind of a lower key treatment
of a more complex topic. So, for example, if you
want to learn the sort of the very fundamentals of
DNA or carbohydrate chemistry, the best place to start is
whatever textbook you use for 51C. Now, I realize, many of you
sold your textbook right after the class was over. That was a huge mistake. But it's not too late
to change things. Number one, I can give you or
loan you a supplemental text if necessary come
to my office hours. First five people that show
up will get one of those. Second, the library-- the science library has
about three shelves that are like this wide that are filled
with organic chemistry text. The exact text does not matter. OK. Basically, if you look at sophomore organic
chemistry textbooks, they're all more
or less the same. OK. What really matters through
is that you have one available to you that you can
refer to as reference. You need that for this class,
OK, because I'm going to assume that you know the
material there. Now along those lines, I've
gotten a couple of emails from some of you
who are concerned. You had trouble with 51C. You had trouble with
sophomore organic chemistry. And now you're taking this sort of advanced organic chemistry
class and you're worried. OK. Here's what I
want you to do. First, don't panic. OK. I will do my best to get
you up to speed on arrow pushing and some other fundamental
comment-- fundamental principles
in the next two weeks. OK. So don't panic yet. At the end of that two weeks,
if what I'm doing on the board and your ability to keep
up in discussion section and on the homework or just,
you know, apples and oranges. You know, fields apart, OK, you're even on the
same race track, then you can start panicking. But for now, no panicking. OK. If you're really, really weak in sophomore
organic chemistry, I'd like you to open the chapters
on carbonyl chemistry. Whatever books it is,
read the chapter-- re-read the chapters
on carbonyl chemistry and get up to speed on those. If you understand how carbonyl
chemist-- how carbonyls react, how the alpha carbon is
acidic and a few other things, you'll be fine in this class. OK. Turns out that's
like 60 or 70 percent of the organic chemistry that underlies biology
involves carbonyls. OK. Start there first. After you finish with the
carbonyls, come see me again and I'll get you up-- I'll
give you the next topic which will probably be amines
or something like that. OK. Sound good? OK. So, hopefully I've
allayed some of your fears. Don't panic yet but get ready
to panic in the next week or so. And also get ready to
take your game up a notch. OK. So, that, you know, even
if you have a bad time in 51C, you can do pretty
well on this class if you're ready to
work pretty hard. You know, do lots of problems, come up with creative
ideas, et cetera. OK. Discussion sections,
these are mandatory. This is especially important if you're weak in
organic chemistry. Discussion sections
are going to be run in a problem solving format
and this is your chance to show that you could do arrow
pushing with the best of them. So, a lot of the problems in
this class involve mechanisms. And so, in discussion
sections you'll have a chance to demonstrate your
ability to do mechanisms. You'll get up to speed on doing
these correctly, et cetera. OK. So, again the
first worksheet will be posted shortly. The first discussion section
will start this Wednesday, Mariam will be teaching
that one. And then after that
it will continue. OK. Now if you're on a Monday-- if you were scheduled for a
Monday discussion section, don't panic, what-- the
material that will be covered on Wednesday well then be
covered on the next Monday. OK. So, we'll have them slightly
staggered throughout the class. OK. And it turns that
actually works out fine because the midterms are on
a Thursday and a Tuesday. OK. So, there will be two
midterms in this class and there are no make
up exams available. They will consist of the
full hour and 20 minutes. There's going to be an emphasis on arrow pushing and
concept problems. There'll be things
like short answer. There will be no multiple
choice, there's going to be like short essay type problems. There'll be problems
where you have to design experiments,
things like that. OK. But lots and lots
of arrow pushing, so get ready for arrow pushing. In addition, the other
way that I'm going to assign your grade is I'll be
looking at two written reports that you're going to
submit in the class. The first of these is a
journal article report due, unfortunately, on
Valentines Day. Happy Valentines Day from
you chemical biology friends. And in this one, in this
report you're basically going to be doing the equivalent of a
book report but using an article from the primary literature
to provide their report. I've already posted to the
website an example of this. In addition, instead
of a final exam, this class will have a
mandatory proposal that's due on the last day of
class, March 14th. OK. So, that's a
mandatory proposal, you can not pass this class
without turning in the proposal. But there's no final exam. The proposal will consist of an original idea
in chemical biology. Now I know this is daunting. I've taught this class before. I know that this is
really intimidating. Don't panic. I will have a series of
exercises for you this quarter that will get you up to the
point where you're ready to come up with creative novel ideas in the cutting edge
of chemical biology. So, you will be ready for this,
you'll be ready to contribute. And the good news is in
chemical biology there's so much that we don't know that's
there's lots of room for smart people
like yourself to come up with really great new ideas. And I see this every year, every year I would take the very
top proposals from this class and I can present them to the
National Institutes of Health and they would get funded. OK. The best ideas I can put
up for faculty ideas anywhere. OK. So, I've seen that before. And the other thing is I'm
looking for a small idea. OK. I'm not looking for, you
know, the next Manhattan Project or something like that. I'm just looking for-- just
give me a base hit, you know, something that will work, that
will teach us something new about chemical biology. And you're good. OK. Quizzes, I will have a
series of quizzes in this class that will number
between one and five, OK, more likely to be one to two. There will definitely be a
quiz sometime in that last week and the reason is our second
midterm is in February and the class keeps
going until March. OK. So, there will
be an easy quiz, the quizzes in general
are designed to be easy. They're basically, you
know, recapitulate something that you just saw on the board. OK. So, we'll run these either
at the beginning of the class, at the end of the class and it'll be something
along the lines of you just saw this mechanism,
show me again how it works, OK, something like that. It just basically
tells me whether or not you're paying attention
and who's showing up for class. And by the way I'm
delighted to see all of you happy people
out this morning. Welcome. But I know
as the class wears on that you guys get very busy. And of course the lectures
will be posted online. There has to be some incentive
here to get you rolled out of bed at 9:30
in the morning. OK. So, we will have
some quizzes. It won't be too many
and they won't be hard. OK. That I promise you. In terms of percent of your
grade, those quizzes only count for 5 percent the same
level of participation. Participation counts on both
lecture and discussion and for that matter even office hours. OK. So me and Mariam and
Krithika getting to know you, that's how we determine
the quiz scores-- or the participation scores. And by the way, I will post
all of these slides online. OK. So, they'll be all
posted to the website so you'll have copies of them. They're not posted now but
they'll be posted shortly. OK. Each midterm will count for
22 percent of your total grade. The journal article report
will count for 16 percent. And then the proposal
which is in place of the final exam counts for
30 percent of your grade. OK. So, it's a pretty even
distribution there're lots of opportunities for you
to get feedback, et cetera. Any questions so far? Yeah. And what is your name? >> Anna. >> Anna. [ Inaudible Remark ] It is. I haven't
talked about that yet. Thanks for anticipating. I'll get to that
in just a moment. OK. Thanks for asking. And Steve? No? What is your name? >> Carl. >> Carl, OK. Carl. [ Inaudible Remark ] Yeah. No problem. Carl's question is
what if I'm assigned to some discussion section that
doesn't fit my schedule, do-- can go to another one? No problem. And you can even
go to one one week and a different one
the next week. No problem. OK. And it is posted
online or it's posted on the syllabus exactly when
the discussion sections will take place. Let met show you that. OK. So, this is the
course website. OK. Notice over here that
there are instructions for the book report. I'll change this very slightly. For 2013, the instructions
for the proposal, I'll change this very slightly. There are three examples
of proposals that got an A and then the syllabus. OK. In the syllabus I've
listed the discussion sections where they meet, et cetera. Feel free to go to any of these. OK. Let me zoom through this. This is online. I'd like you to read
this carefully. I'm going to hold you to all of
the provisions that are in here. OK. So, anything
that's written in here, it's the equivalent
to me saying it. All right. I'm not sure exactly why
it is that's been cut off in the right. A lot of this recapitulates
what I've just said. OK. Let's get to
this, Anna's question. Over here, there
will be-- let's see. One moment. OK. On February 21st,
2013, you will turn in an abstract for
your proposal. OK. So, an abstract
is a short condensate of what your proposal
is going to consist of. This tells me whether
or not you're on track. And I'm going to
use this as a way to give you early
feedback about your idea. And tell you whether or not
I think your idea fits the definition of chemical biology. Whether or not I think
your idea is a creative one or not so creative. OK. So, this gives me a chance to give you feedback before
you turn in your proposal. OK. And this abstract is
worth 10 percent of the points for the proposal assignment. OK. So, in other words 3 percent of your course grade will be
determined by that abstract. OK. Note that all
assignments are due by 11 a.m. on the due day. There is a late policy. But I hope that doesn't
apply to you. Questions so far? All right. Yeah? No. Just stretching
all right. There's some information
here about adds and drops. There's a frequently
asked questions section. Do I need to attend
discussion sections? Yes. Discussing paper,
turning the final assignment. Oh, if you have not taken
all three quarters of Chem 51 or two semesters of
sophomore organic chemistry. You should drop the class. OK. You're going to
blown out of the water. OK. So, you must
drop the class now. It's a prerequisite and
then every year someone slips through. Don't take this class if you haven't taken the
full sophomore organic chemistry series. OK. OK. There's a whole thing
on incompletes over here. Academic honesty. Unfortunately, we're
going to talk about this later in the class. I do not want it
to apply to you. Major portion of your grade is
going to be writing assignments and so academic integrity
issues loom large unfortunately in this class. Every year, I have to
give someone F grade on the assignment which ends
ups turning into like a C minus, D plus kind of deal because they
try to plagiarize assignment. Don't let that be you. Let's make this the year where
I don't have this problem. Along those lines,
if this is the year where I don't have any
plagiarism problems, I will give an additional
3 percent higher grades. So, I'll assign the grades
and then I'll go through and I'll bump up 3 percent
of the course grades to the next higher grade. OK. So, if everyone in the class
avoids having any plagiarism or academic honesty issues. So no cheating on the
exams, no plagiarism, no academic honesty I will bump
up the grades by 3 percent. OK. That means four, five of
you at each level are going to get a higher grade. OK. So that means like four
people, three or four people who are going to get a B plus
I'll move them up to A minus. I'll take top-- the three
or four top A minuses and move them up to an A. OK. That's the deal. OK. We'll talk some
more about this because it's a slippery slope
and it's best that we don't have to have this conversation later. OK. So, anyway, that's the
information on the syllabus. I'm holding you entirely to
the contents of that syllabus. So I'm expecting you to go home
and read the syllabus carefully. I don't have time to talk
about every aspect of it now. I'd like you to go home though
and read it carefully please. OK. Questions? Questions? OK. Skip that, skip that. OK. Let's get started. So, we already heard
the question, what is chemical biology? How does it differ
from biochemistry? I gave you kind of
a quick answer. I want to delve into this
topic a little bit further. OK. So, here's the working
definition of chemical biology that we'll be using in this
quarter and it's important that you understands this. This is the definition is using
chemistry to advance an under-- molecular understanding
of biology at the level of atoms and bonds. So, the way I know that
we're talking at the level of molecular-- at the molecular
level is if we're talking about atoms and bonds. OK. And that's what I'm
looking for in terms of a definition of
chemical biology. There is a second
corollary to this definition which is using techniques from
biology to advance chemistry. And some examples of
these are, for example, using molecular biology
techniques to develop combinatorial
libraries of chemicals which is something that
is one of the projects that my own laboratory does. OK. So, there are
two parts of this. Using techniques from
chemistry to study biology or using techniques from biology
to solve problems in chemistry. In both cases, these
involve looking at molecules at the level of atoms and bonds. And that's where it's
distinct from biochemistry. Biochemistry also uses
techniques in chemistry but oftentimes, they're content
with looking at molecules as sort of amorphous blobs that
are represented as, you know, spheres or something
like that in textbooks. In this class, we'll be down
at the level of atoms and bonds and that's how you know we'll be
talking about chemical biology. So, later in the class when I
ask you to come up with an idea in chemical biology
a proposal idea, then you should be thinking at
the level of atoms and bonds. And then that tells you whether or not your idea
will be acceptable. OK. So, chemical biology
advances both chemistry and biology. And I wanted to give
you a couple of historical examples to this. For my money, the very first
chemical biologist was Joseph Priestley, this guy over here. He was a remarkable character. So, he isolated oxygen
and other gases. OK. So, he was isolating
these using electrolysis and other techniques. And he would isolate
these in bell jars and then he'd use these
chemicals to study biology. So, one of the experiments
he did for example was subjecting poor
mice, mice that he would trap from fields to these different
chemicals that he was isolating. And he found that the mouse
for example can live in oxygen, but could not live in
many of the other gasses that he was isolating. OK. So that's a really
interesting example because he's using the very
latest techniques from chemistry to understand better
how respiration works. How organisms take in
oxygen and at the same time, it's using a technique
from biology as a way of solving a problem
in chemistry. And the technique in biology
is, does the mouse live or die? Does the organism-- can
the organism survive under these conditions
to tell me something about those chemicals, right. Joseph Priestley didn't have any
spectroscopy available to him. So, he is using a
technique from biology, a very qualitative
technique to be sure by the method nonetheless
to tell him something about what's happening
at the chemical level. OK. Now Sir Joseph-- or Joseph
Priestley had some radical ideas about colonist in America
and theological descents that were going on in
England at that time. And I like to say that the very
first chemical biologist had his house burned by an angry
mob who came rampaging through his village
with pitchforks and were out literally to get his head. And we had a proud
tradition ever since of iconoclastic
thinkers and independent people who were guaranteed
to rile up the masses. But of course, he's
not getting burned at-- or his house is not
getting burned because of his chemical virtues. This was then carried on by Sir
Humphrey Davy who's shown here at Royal Society of Chemistry
conducting the experiments on his colleagues. He's having them
inhale bags made out of silk that include gasses. And then he's looking at
the violent excretions that happened afterwards. And so, this is just a classic
woodcut from the period. OK. Now, the other-- so, these
are sort of early workers. Perhaps historically, the
most important experiment in chemical biology was done by the great Friedrich
Wohler in 1828. Here's a picture of him. Notice that these
guys are pretty young. OK. These guys, you know, they were doing these
stuff in their 20s. OK. They're not much
older than you. Any of you in this
classroom five years from now, you could also be doing stuff that would change how we
think about the universe. OK. That's the way
science works. That's one of the great
things about science. OK. So, don't think about this as being done only
by old people. It's not. It's done-- These
great ideas are often times done by young iconoclast
who have clever ideas and just want to
push the balance. OK. So here's Friedrich
Wohler, 1828, he is running an
experiment in his laboratory where he's running this
silver cyanate experiment where he's trying
to do what would like just the most pedestrian
of exchanges of salts. OK. So, what he's trying to do is synthesize ammonium
cyanate using silver chloride which he knows will
precipitate out. Recall from Chem 1
that precipitates out in a white powder
and he's doing this by simply mixing silver cyanate
together with ammonium chloride. And he's expecting
when he heats this up that the silver chloride
will precipitate out and he'll be left
with ammonium cyanate. It turns out that's
not what he got. OK. That was not the
product that occurred. Instead, what happened was
he got out this other product that crystallized out
of the reaction flask. And when he smelled
this other product, he knew immediately what it
was, what he smelled was urea. And urea had been isolated from
urine, from dogs and humans. And so it was known that
urea is a known compound. And back then, the primary way of characterizing the
chemicals was by their smell, by their taste, you know, some
gross physical properties. And because urea has
a distinctive smell, he can readily characterize
this. Now, here's the significance
of this discovery. What Friedrich Wohler recognized
was that this urea was identical to the urea that's attained
from dogs and from humans. But the difference is this did
not come from a living organism. In other words, using
just mineral sources, you can make the same chemicals that are found in
living organisms. So, there's not some
sort of special property that animates the
chemistry of living organisms that some how makes it special. Instead, it's going to be
governed by the same rules that are found in chemistry
that's outside living organisms. OK. And this is really
important because at that time, there was this notion that living organisms would
have some sort of special spark that in someway would make
them alive and make them-- make their chemistry
unique and special. And what Wohler is showing
us by this experiment, is that in fact there was
nothing unique and special about the chemistry
inside living organisms. OK. So, these are great
examples of using chemistry to understand biology
at the level of atoms and bonds in the case of urea. Let's move on. Another principle that underlies
chemical biology is evolution. We're going to be talking a lot
about evolution in this class. And so the reason we're going
to be doing this is first, it simplifies knowledge. And second, it's going to
guide experimental design. And here're two views of
the great Charles Darwin. We can't talk about evolution
without making reference to Charles Darwin who
articulated in, you know, 150 years ago, much-- you know,
the principles behind evolution. There are two steps
to evolution. The first step is to diversify,
to generate a diverse population of molecules, of organisms,
of phenotypes really. And then the second step is
to select for the fittest from this diverse population. I'll explain the word phenotype
in a moment don't panic if you didn't understand
that word. So, there're simply
two steps here. Select for-- generate
diversity, select for fittest. These steps are then
repeated again and again to evolve organisms that can
solve some sort of problem. In terms of chemical biology, we think about generating
diverse populations as ways of shuffling together--
shuffling around biooligomers in combinatorial manner,
in combinatorial manners. And I'll show you
that in a moment. And we often do experiments that involve some
selection for fitness. We're going to make a large
population of molecules, mix them up and pick out
the ones that are most-- that can best fit a criteria
or set of conditions. This is a very powerful
principle that allows us to make progress very
quickly in chemical biology. And this is used as a
technique by hundreds of laboratories in the field. OK. So, we use evolution
not just system sort of theoretical underpinning. But we also use this as
an experimental framework. And I encourage you when you're
thinking about proposal ideas, think about evolution as
a tool to help you speed up getting towards molecules
that do stuff for you. OK. So this is used extensively. Another way that's used
extensively is it's used to organize knowledge. When we talk about say the
ribosome, which is the machine that translates mRNA
into proteins. And I'll show you what that
looks like in the moment. I don't have to talk
to you about some sort of special ribosome that's found
exclusively in humans or dogs or something like that. Because it turns out that the
same mechanism used by ribosomes in humans is also
used by bacteria. It's even the same mechanism
used by Archaebacteria, a different stem on the
tree of life entirely. And so, what this means then is
that, I don't have to teach you about the special
chemistry of humans. I can talk about the chemistry
that underlies on all organisms on the planet because we all
evolved from common ancestors that solved these mechanistic
problems in chemical biology. OK. So, this provides
the powerful approach to evolve molecules
which I alluded to in the previous slide,
but equally importantly, this helps us to
organize knowledge and make it much
simpler for us to talk about universal chemical
mechanisms that underlie all
life on the planet. OK. So, speaking of sort
of universal principles that underlie all life in
the planet, the Central Dogma of Modern Biology is use-- is going to appear in multiple
ways throughout this quarter. In the first way, this is how
we've organized the textbook that we'll be using
this quarter. OK. So, the textbook
has different chapters. And it's organized according
to the Central Dogma. So, the Central Dogma
describes all biosynthesis that takes place in
cells and on the planet. OK. So, everything that
you're going to synthesize in your cells is in some way
encoded by this Central Dogma. The Central Dogma tells us
that the DNA found in nuclei in eukaryotic cells
is the blueprint upon which all biosynthesis is based. This DNA is transcribed into RNA and then translated
into proteins. OK. So, this is the
earliest diagram by the Great Francis Crick who recognized the far reaching
implications on this Dogma. Very early on, OK, this
is his earliest example of where it was articulated. It looked just like this. We know now, for example,
that there is in fact-- this dash line over here
is in fact a real line. There is an enzyme
reverse transcriptase that can convert RNA into DNA. But this line over here
where RNA is used a template to make new copies of it self,
this line never materialize. We have not found it in
many years of looking. In fact it would be a great
chemical biology proposal to come up of the
way of doing that. OK. So here's a different
way of looking at the Central Dogma
of Modern Biology. So, at the very top, DNA, this
biopolymer up here is going to encode messenger RNA
and in fact all RNAs. This-- The conversion of DNA into the complimentary RNA takes
place using an enzyme called RNA polymerase. OK. This is nice
because it's going to be polymerizing
RNA, this make sense. I'm going to be referring
to enzymes today and in future classes,
enzymes are proteins that catalyze chemical
transformations. OK. So, these lower the
transition state energy for key reactions that
take place in the cell. And here's our first
example of this. The enzyme RNA polymerase that's
responsible for transcription. In addition, there's an
enzyme DNA polymerase that allows replication of
the DNA to make new copies of the DNA when the
cell has to divide. OK. Here's the ribosome
that I alluded to earlier on a previous slide
that is responsible for translation of
RNA into proteins. This Central Dogma continues as proteins then can
catalyze reactions that lead to other biooligomers
that are going to be very important
in this class. For example, we're
going to see a class of biooligomers called
terpenes that are used in-- used by plants and
microorganisms for signaling. Polyketides, a class of
molecules that's very important as natural products
for antibiotics and other pharmaceutical uses. And then oligosaccharides, the glycans that decorate
the surfaces of your cells and play key roles in
protein folding and key roles in cell base signaling. OK. So, here's my
plan for this quarter. We're going to have
two lectures about each of the biooligomers
that's depicted here. OK. So, next week, I'll talk two
lectures about arrow pushing. Week three, we'll have
two lectures about DNA. Week four, two lectures
about RNA. Week five, two lectures
about proteins. Week six, oligosaccharides. Week seven, polyketides. Eight is terpenes. Oh, actually, I'm sorry. I'll have four lectures
total about proteins. I can't resist. I'm a protein guy. So, yeah, so we'll have a total
of four lectures about proteins, but everything else we'll
have two lectures about. And we'll be covering a
chapter a week in the class. OK. So, necessarily
some of the material of the textbook will
be left aside. OK. Everyone still
with me so far? >> Yes. >> OK. So I told you that
everything that synthesized in the cell is synthesized
in a deterministic way, starting with the DNA up here. And it turns out that's not
strictly, strictly true. And I want to explore
a little bit more about what the subtleties
of this concept. So, first of all, we need to define what is the
unit of synthesis? So, proteins and DNA, oh sorry, DNA is read out in
units called genes, OK, where each gene is going
to coat a single protein. Genes have two essential
parts, an on-off switch and an express sequence. The on-off switch is where
transcription factors bind. These are proteins that can
encourage RNA polymerase to bind to the start of this
gene and encourage it to start transcription. OK. Similarly there's
other-- if there's promoters, there's also other ways of shutting off the
synthesis as well. It gets complicated. This transcribe region then
becomes the messenger RNA which is then translated
by the ribosome into the protein down here. OK. So, here is an example for a transcription
factor binding to DNA. Notice that the DNA
has a structure that can nicely accommodate
the structure of this protein. I'm going to be talking a lot
more about proteins later. But I want to tell
you about a convention that we're going to be using. OK. So, proteins hopefully
as you know are composed of amino acids that are strung
together by amide bonds. OK. If what I told you totally
doesn't make sense, read-- go back and read the
reference supplemental organic chemistry text. OK. So, when we look at these
amino acids and we just look at the amide bonds and
the carbon that's alpha to that amide bond. We can trace out that back bone
using these ribbon structures. So, these ribbon structures
do not look at the side chain of amino acid, rather they
simply trace out the sort of the scaffolding back
bone of the protein. OK. So, that's what these
ribbon diagrams will look like. And then here's a
structure of DNA down here. Notice that this alpha
helical ribbon, this curly, cute ribbon fits neatly
into the DNA's major grove. We'll talk much more
about that later. OK. Let's take a look at
the world's smallest gene. This is the Guinness Book of
World Records for smallest gene. In this case, this gene encodes
for microcin C7 or the gene-- the protein it will encode
for is called microcin. Microcin is a translation
inhibitor. It's a protein. It's-- Well, it's a peptide, short piece of protein
called a peptide that's used by microorganisms to
kill off their neighbors. OK. So, the microorganisms
that grow in your skin, that grow in the, you know,
far recesses of this-- of the walls, you
know, that grow all around you are constantly
fighting chemical warfare with each other. OK. Their goals are to
kill off their neighbors and then give themselves more
resources that allow them to grow better, OK, to grow
faster and to be more populous. OK. And microcin is
a good example of one of those antibiotics
or compounds that kill other organisms. OK. And this is actually a
very complicated binary toxin. On the one hand, there's
this peptide over here that allows the microcin
to be transported into the competing bacteria. OK. So, the bacteria, look
at this complicated thing, they sniff at the peptide
region and think, "Oh, that peptide looks yummy. And if I eat that, I'll
get amino acids as a source of building blocks
for my own proteins." OK. That's kind of
like the bait. OK. So, the competitor
picks up the bait, transports microcin into--
the microcin c7 into it-- into itself and in which case, enzymes in the competitor then
break a part this peptide. And then unveil the translation
inhibitor down here that shuts down translation
by the ribosome. This is very bad news for
the competitor, right? If the competitor organism-- microorganism can not
translate mRNA into proteins, it cannot live, it
cannot divide, it will die very quickly. OK. And so, in the end,
what we're seeing is that the smallest gene
is rather complex. Its toxic fragment is
highlighted over here and the rest of it also
plays a key role as well. OK. So, this-- to make
something as complicated as this requires a large
number of genes that are lined up over here where each one of these arrows represents
a sequence of DNA. OK. And we'll talk more
about the directionality of the arrows, you
know, later, week three. For now don't get too
worked up about it. Notice though that it
takes several genes to compose this toxin. OK. So, some of these genes
are doing things like adding on this non-peptide
like toxic fragment. OK. So, some of these genes up here are encoding
various enzymes. OK. So that's this microcin,
this mccB, mccD, mccE enzymes. So these enzymes are adding on
stuff and modifying the peptide that was otherwise encoded by
mccC in the center over here. OK. I'm sorry, mccA that
was encoded up here. Now, at the end of this, even though this is
the world's smallest-- you know, smallest
gene delivering a tiny little peptide. The resulting peptide is
still fiendishly complex. OK. This thing includes
a large number of different stereocenters
indicated by the dashes and the wedges. And furthermore, this isn't
the half of it, right. This is just very
simple example. The proteins we'll
be talking about, the proteins I've been
showing you today, for example, the transcription factor,
consist of hundreds of subunits, hundreds of amino
acids, each one likely with its own stereocenter. And so the chemical biology
considerations become enormous when we start looking at
this in greater detail. OK. All right. So, we've looked at a
gene let's talk next about the collection of genes. All of the genes
together that are found in an organism are
referred to as a genome. Here's one representation
of the genome of the bacteria model system,
bacteria called E. coli. We'll be talking a
lot about E. coli. I'll have another slide
about it in a moment. This is used extensively in chemical biology
laboratories including mine. And its genome looks like this. Where in this representation
it's shown as a circle and each one on these colored
bars tells us something about the size of the
gene, whether not it's GC-- whether it's GC richness
is, et cetera. OK. So, reading out
the information here, not so important. Suffice it to say that
the human genome has around 24,000 or so genes. And when you compare that
against almost any other machine that we have around us, this number sounds
ridiculously small. One of the challenges, however, is even though we have
this complete parts list for a simple organisms
like E. coli, it's not clear what each
one of these parts is doing. And so a goal of functional
genomics and a goal for that matter of
chemical biology is to try to make better sense
of this parts list. OK. And let me show you what
I mean on the next slide. OK. Let's imagine that you
had a transmission from a car. OK. And imagine that
you had parts list of all the different gears
found in that transmission. OK. I could tell from some
experience that just starring at those different gears, even,
you know, starring as hard as you possibly can and
using your best, you know, sort of logical reasoning,
you're going to have really, really hard time trying
to put together each one of those little gears. OK. I don't care
how smart you are. It's a really hard problem. And so, we have that same
problem when we look at genomes. When we look at genomes,
it's not clear what each one of these parts are doing. And one of the roles
of chemical biology is to help us annotate genomes and
teach us about what each one of those parts is doing in
terms of the larger machine. We'll talk some more about that. There'll be a topic
called Functional Genomics. OK. So chemical biology
helps us fill in the dynamics of the process and how
these pieces fit together. OK. So, one way that
it fills in dynamics, dynamics means change
overtime is an important area of chemical biology develops
new tools that allow us to see molecules at the
single molecule level and understand how
they change overtime. How they dynamically
interconvert it to different speeds
and things like that. And Mariam is one of the
world's experts at this. She can tell you
more about this. Now, another big
challenge that we have is that often times we have
big differences in genomes that lead to the same species. Here for example are
three different strains of the model bacteria, E. coli. OK. So, here're three different
strains and only 40 percent of proteins are shared
between these three. Notice that they look identical,
they're all the same species because they can mate, they can
exchange DNA with each other which in terms of bacteria turns
out is not necessary the same as being same species. But in any case, these are
named-- all named E. coli, yet they have vast differences
in what DNA they've picked up from their environment and
from other microorganisms. So, simply knowing the parts
list is not going to be enough for us to explain what's
similar and different between these organisms. OK. And for that matter when
we start looking at different-- when we start looking
at different organisms from the same population,
we see a similar sort of diversity despite
having very, very, very similar genomes. OK. So, I've been
talking to you both about humans and also bacteria. I need to hopefully just
very briefly review for you that the differences in
those organisms are vast. OK. I'm hopefully not
telling you anything you don't already know. Bacteria are classified
as prokaryotes, humans and other multi-celled
organisms or organisms even that are single cell that
have multiple compartments in them are classified
as eukaryotes. I'd like you to or I'll
tell you that in a moment. The big difference here is that the prokaryotes don't
have any compartments for the most part. The DNA has kind of
organized into nucleoid, but for the most part there are
no compartments in the inside of the cell of a prokaryote. Whereas when we look at
eukaryotes under the microscope, we find something
totally different. What we find is a
bunch of organelles which are these little
compartments in here. OK. And these organelles
have different functions for the cell rather than being
just the big bag that has all of the functions
being carried out kind of randomly within that bag. OK. Now, getting back
to this idea of genomes, nearly identical genomes can
lead to very different people. So, even though our genomes are
99.9 percent identical we see vast differences. So, this is a challenging
concept but what's happening
here are vast differences in transcription underlie
these different phenotypes that are observed where phenotype is the
physical outcome of the gene. OK. So all of us have
roughly the same genomes, yet the phenotypes that come
out differ at the cellular level by different transcription
levels that program our cells into having different functions. So, even though each one of
these cells has the same genome that cells end up having
different functions by having different
transcription levels of different sections
of the gene-- different genes within
the genome. And furthermore at the
organismal level this plays out in other ways as well, OK, also at the level
of transcription. OK. So, here're six
different human cells and you can see vast differences
in their morphologies, their shapes, et cetera. And for that matter, I don't
think I have to work hard to convince you that these have
very different functions inside the organism, in
this case humans. OK. So, I showed you briefly
a prokaryotic cell over here, I'd like you to memorize
all of the structures. Everything that's labeled
here and labeled in the book-- the textbook, OK, you should
memorize the structures. And along those same
lines I'd like you to memorize all the
parts that are labeled in the textbook for
eukaryotic cell. OK. So you should know basically
the simple anatomy of a cell. OK. >> Do you know its
functions as well? >> The basic functions. If it's in the book,
yeah, I like you to know. OK. So, we've looked at DNA. DNA gives us genes,
which gives us genomes. Next section down on the
Central Dogma is RNA. So, from RNA the complete
collection of RNA transcripts in a cell tissue organism
is called the transcriptome. OK. So here's the DNA, the
genome of the organism. Here's a bunch of RNA
transcripts and the number of copies that each one of
these transcripts is controlled by transcription factors
that I showed you earlier. OK. That was the alpha helix
fitting into the DNA. If that transcription factor
is very effective at grabbing on to RNA polymerase then
you'll get more copies of the mRNA transcript
being produced. OK. So these more copies of the transcript being
produced can give rise to very different
phenotypes of the organism. So ultimately a lot
of the phenotypes that observed are being driven
by differences in transcription, in addition to differences
in the encoding DNA. Everyone still with me? OK. Things are going to
get a little bizarre next. It turns out that the
RNA that's encoded by DNA is further diversified by
a process called RNA splicing. OK. So RNA splicing takes the
RNA that's encoded by the DNA and then sort of shuffles
it around very subtly. OK. And the results are a bunch of different mRNAs encoding
potentially different proteins down here. OK. And the results sometimes
are dramatically differences in the result in proteins. So these proteins,
the consequences in this can be proteins that
have very different function from the starting mRNAs. You can end up with two
different proteins splice variance of each other that
are encoded by the same DNA that have different
results inside the cell in different phenotypes. OK. Now there's going
to be further diversity but just to organize things. So we've seen at the DNA
level, the collection of all genes is called
the genome. We've seen at the RNA
level, the collection of all RNA transcripts is called
the transcriptome and then at the level of proteins,
the collection of all proteins is
called the proteome. OK. This is-- There is a sort of a neat organization
to all of this. OK. Now what I'm showing you, I've already showed
you this representation of the genome for E. coli. This is a way of representing
the transcriptome using a technique called
RNA microarrays. We'll talk about this
more in week four. And then you can do a similar
thing that make a big collection of all the different proteins
found in the cell of organism or tissue and array these on
microscopic slides as well. OK. So, all these techniques
are ones that we'll talk about later in the class. OK. So we've talked
about how you can start with an RNA transcript. Oh, question over here. >> I just wonder what
the RNA splicing-- >> Yes. >> -- for the message RNA. [ Inaudible Remark ] >> OK. So what is your name? >> Ashley. >> Ashley. OK. So Ashley's question is
what actually gets translated on the messenger RNA? >> Yes. >> And-- [ Inaudible Remark ] And there's what? >> In translating the mRNA. >> Yes, what actually gets
translated into proteins from the messenger RNA? OK. That's your question right? >> No. >> No. [ Inaudible Remark ] Yes. [ Inaudible Remark ] The axons? [ Inaudible Remark ] Oh, OK. So your question
is more subtle than that. OK. So could I defer
that until we get to week four which is the RNA? >> OK, yeah. >> OK. Good question. We'll get an answer. Other questions? OK. So we've seen how splicing
can start with transcripts and then add additional
diversity. It turns out that
proteins are also subject to diversification as well. So after the proteins
are synthesized by the ribosome during
translation, these are subject to further diversity in a
couple of different ways. OK. The first way
is for the proteins to be modified chemically
on their surface, and so one example of this
is an elongation factor II. So this is posttranslationally
modified to produce this functionality
up here called diphthamide. OK. So the protein is
enzymatically converted from having this imidazole
functionality up here into having a diphthamide
functionality. This is absolutely required for
translation by this organism, organism being humans. OK. So elongation factor II
that's been posttranslationally modified is required for
translation to take place. However, the diphtheria
toxin has a way of cleaving off this
diphthamide. OK. When that happens, that prevents protein
translation from taking place. OK. Diphtheria toxin
fascinating, it's an effective
way of killing cells. What's important here though
is this notion that even after the proteins
are synthesized, they're further diversified
by chemical reactions that take place on
their surface. Because this takes place after
translation, these are referred to as posttranslational
modifications. OK. Post meaning after;
translation, modifications. Translational modifications. And this is really important. This means that we can start,
let's say, 24,000 or so genes in the genome get,
you know, say 50,000 or 60,000 different
splice variance, get say 60,000 different
proteins and then further diversify
those 60,000 different proteins into to 200 or even more
thousand different proteins. So in the end although our
genomes look relatively uncomplexed at the level of
24,000 or so different parts, the true number-- this vastly
understates the true number of parts which is
much, much larger due to reactions like this one. OK. Furthermore,
these proteins go off and catalyze other functions within the cell leading
to further diversity. OK. Everyone still with me in the posttranslational
modification? Let me show you what I mean. I refer to this as
posttranslational processes. So, this is the process by which
proteins catalyze as enzymes, the production of other
molecules, oligosaccharides, glycans, polyketides
and terpenes. OK. So, once the enzyme is
made, it's just the start. After that, all kinds of
other things take place. OK. And this is-- proteins
can be covalently altered by enzymes. OK. That's the modified
proteins that I showed you on the previous slide. In addition, there are
spontaneous processes that alter the surfaces
of proteins. OK. So, for example,
oxidation of proteins is sort of an unavoidable consequence of having a metabolism that's
dependent upon oxidation, right, and producing oxidation
products. So, there are some
strong oxidants that are produced by your cells. And those oxidants will come
along and modify the surfaces of proteins, spontaneously, OK, using thermodynamically
accessible reactions. And so these are examples of
posttranslational modifications. In addition, proteins themselves
will catalyze reactions that will synthesize
these molecules down here which again are part of the Central Dogma,
their biooligomers. Now, one thing I have to tell
you is that while I told you that the Central Dogma in a deterministic way
determines everything that's been synthesize by the cell-- while it determines everything
synthesize by the cell, it's not purely deterministic. OK. And there's an element
of randomness to all of this. OK. And that's what I want
to show in the next slide. OK. This is-- we're going to
have randomness in the sense that the Central Dogma will
dictate the identity of enzymes and then these enzymes are going
to go up and catalyze reactions that will not be
determined by the DNA. That will be at some level
a little bit randomized. OK. So, one good example
of this is the process of appending oligosaccharides
to the surfaces of proteins. OK. So, R over here is meant to
represent a protein and each one of these shapes is meant to represent a different
carbohydrate, glycan, that's being-- that's
going to be attached to the surface of the protein. OK. Now, the way this
works is that each one of the enzymes that's going to
do this attachment is encoded by some gene up here, encoded
by the DNA, translated-- transcribed into messenger RNA
which in turn makes the protein, the enzyme that's going
to catalyze bond formation to add this glycan onto
the oligosaccharide. OK. What's less clear though
is, you know, small variations in the resulting
glycans down here. So, for example, enzyme
2 makes this bond, if there's enough enzyme 2 around maybe it makes
another bond. Enzyme 11 makes this bond, but maybe if there's
enough enzyme 11 around maybe it makes
another bond over here. So, there's diversity in
the resulting structures that are biosynthesized
by the enzymes. OK. Furthermore, even though
I'm lining up the enzymes in this order, the order of the
genes in the genome is unrelated to the final product that
results in this glycan on the surface of the protein
which eventually appears in the surface of the cell. So, there is considerable
heterogeneity in these posttranslational
processes. Both in terms of modifications
in the sense that some of these modifications are
occurring spontaneously just through thermodynamically
accessible reactions. And furthermore, when these
posttranslational processes are catalyzed by enzymes, there
is considerable stochasm, randomness in terms of what the
resulting structures will be. OK. So this is one of these
kind of mind-blowing concepts that we have to get
comfortable with. OK. That we can't in a deterministic way
know every single molecule in a cell to a precise level. OK. Everyone comfortable
with that concept? OK. Don't look so
moppy-eyed and downcast. At the end of this
class, hopefully, you'll at least have a
framework to understand it, OK. OK. So, I want to
switch gears now and talk about some other principles,
different types of techniques that you need to know that
are going to make our lives so much easier in understanding
the experiments behind chemical biology. OK. So earlier, I told you
that an important principle in chemical biology or an important technique
used extensively in chemical biology is
to make large diversity, a large diversity of
molecules, and then sift through this diversity
to find a few molecules that do something special. OK. This is a technique
of molecular evolution. It's used extensively
in chemical biology. So, there's going to be one
equation in today's lecture that I need you to know. And this is the equation
that determines the diversity of a collection of molecules. That diversity, the
number of oligomers that results is the number of
subunits raised to the power of the length of the oligomer. OK. And let me try to
show you this in action. OK. So, let me turn
on some lights here. OK. So let's start with DNA. Let's make a big
collection of DNA. So, DNA consist of four bases,
OK, A, C, G, and T. Again, we'll talk some more about their
chemical structure in a moment. Let's try to imagine then that
we're going to make a collection of all possible tetramers. OK. OK. Number of possible DNA. Let's make it pentamers. OK. OK. So the number of
possible pentamers is going to be equal to the
number of subunits raised to the length of
the biooligomer. OK. So, this-- the number
of sub units is four, that's the number of bases. The-- Raised to the
power of 5 that's because we're making pentamers. OK. If we wanted to make-- OK,
so this is example of five-mers. If we want to do
ten-mers, again, we'd have 4 raise
to the 10th power. OK. OK. So this is a very simple
equation, very, very useful. It can tell you very
rapidly whether or not the experiment you've
proposed is reasonable, right. If you propose something,
that's going to fill this room with DNA probably not
so reasonable, right. That's not practical. But if you propose something
that you could fit and say, a 1 ml test tube, totally
reasonable, or 1 ml tube, [inaudible] tube,
that would work. OK. OK. Any questions
about this formula? You ready to apply it? OK. Good. OK. One of the great feelings
of teaching a class like this one is that the
example problems that I'll do for you where we applied
equation or whatever, inevitably are a lot
easier than the ones that appear on the exam. And I apologize about that. That's kind of-- that's
part of pedagogy I guess. OK. Now, it turns out that
chemical biologists apply this to DNA, but they also apply it to much more complicated
molecules. So for example, we can do
a combinatorial synthesis of a series of molecules
that look like this. OK. So, we could do, we can
setup a modular architecture to allow combinatorial
synthesis that in a way similar to composing biooligomers
will result in molecules that have modules that have
been tethered together. OK. So for example, this is-- this is a framework
called the peptoid. OK. And so instead of a peptide where the peptide would
have a side chain coming out on the alpha
carbon over here. Instead this had side chains
coming out on the nitrogens. You can very readily make a
large combinatorial library of these peptoids and
make a great diversity of number structures using
exactly the same formula that I showed on
the previous slide to calculate the
result in diversity. OK. And let me show
you how that work. If you have 20 subunits, so you have 20 different
possible building blocks, and you're going
to make three-mers, then you would have
20 to the power of 3, 20 raised to the third
power would be the result in diversity of that library. OK. Where a library is a
collection of diverse molecules. OK. So, this idea of combinatorial diversity
applies both at the level of shuffling around biooligomers
and is applied in biology. But equally importantly
it's used as a principle that underlies chemical
synthesis in chemical biology as well, including
the chemical synthesis that you learned
about back in 51C. OK. And we can get much more
complicated and make libraries of benzodiazepines
which are shown here. And this is an important class of small molecules
that's very commonly use in many different drugs. OK. Why don't we stop here? When we come back next
time, we'll be talking about diversity of biology. [ Silence ]
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