This is a message that I posted to the United Devices Member Message Board on April 10, 2001, to help other volunteers in United Devices’ distributed computing project understand what was meant by the term “conformer” that was appearing on their display screens. I’ve included a few messages that appeared just ahead of mine.
From: http://forum.ud.com/ubbcgi/ultimatebb.cgi?ubb=get_topic&f=10&t=000042
Blue Lion
posted 04-04-2001 06:20 PM
I've read the FAQ and it's still not
clear. Can someone who knows please explain...what, exactly, is a conformer?
Rob M
posted 04-05-2001 03:36 PM
Ok, some quick molecular mechanics...
For the simplest molecule with two
atoms (a diatomic) we only need to describe one parameter, the bond length
between the two.
For a linear triatomic we need two
bond lengths and for a non-linear triatomic we need two bond lengths and a
dihedral angle .
For a four atom molecule we need:
Three bond lengths, two dihedral angles and a torsion angle. And for each
further atom beyond 4 we need another bond length, dihedral and torsion angle.
So for 20 atoms we need 6 + 3*16 = 54
parameters to describe the conformation. Now consider how small changes in
bonding angles can add up to change the shape of the molecule and how
complicated searching through the parametric space is...
And this is all before you get to the
binding evaluation...
Halon50
posted 04-05-2001 08:13 PM
*blinks slowly*
So, uh, you're saying that the molecule
thingy gets attached to the protein thingy, and something happens?
*scratches head*
-Tex
Nadim
posted 04-06-2001 02:20 AM
Wow, Rob... I thought that simply
signing up for an Organic Chemistry class was a sign of masochism. And to think
that you actually went to class, and even more impressively, stayed
awake!
My background apparently hasn't
prepared my brain to "conform" (sorry...) to the paradigms of this
field...I'm still trying to figure out which symbol on the 3d model represents
a transistor.
Rob M
posted 04-06-2001 03:17 AM
Okay, maybe a bit too technical
As for the organic chemistry
masochism, I totally agree. Which was why I slacked off in computational
chemistry instead!
So the next question is why do I now
work as an organic chemist...
Wayne Farmer
posted 04-10-2001 10:41 PM
Rob, although I'm a computer
scientist, not a molecular biologist, I'd like to also try to help folks
understand. Please correct me if I make mistakes!
Let me begin by suggesting a way to imagine
what is happening when you're creating conformers of a molecule. Imagine that
you're holding a model of the molecule in your hands, just as it looks on your
THINK screen. Now, imagine that the little colored balls in the model (the
atoms of the molecule) are really magnets that may repel certain balls, but may
attract others. Then imagine that the little sticks that join the colored balls
(the molecular bonds) are little coiled springs like the kind you find in a
ball point pen.
Hold this whole mess in your hands,
and start to squeeze and fold it in different ways, or hold part of it while
waving the rest around like a flag. Guess what -- some of your squeezings and
jigglings will pop back into the original position, but some will clump
together into a new position that will want to retain its new shape.
Congratulations! You've just created a new conformer!
You can see that, for a large
molecule with many atoms, there can be a lot of new positions that will
want to retain their new shape. (I guess Rob would call these "stable
configurations".) Each different shape will therefore have a different
"fit" when it is placed up against the superoxide dismutase protein.
THINK is trying to find a molecule that will have a really good fit against
that protein, especially a fit so good that the protein would prefer to grab
and hold on to that molecule instead of grabbing and holding on to the
one it would in a human body not receiving any of our molecules in
chemotherapy. A good fit is a "hit"!
Why are we doing this? We're trying
to "jam up" the superoxide dismutase proteins throughout the cells in
the human body, and make them inactive. Those proteins do a major part of the
"garbage collection" in human cells, and if the garbage collectors go
on strike, you know what happens: the cell fills with garbage and soon becomes
a place where nothing can get done. This can be a good thing, though, because
cancer cells make garbage faster than normal cells, so they're the first to die
if the garbage collectors go on strike. So the idea is to feed our
"hit" molecules as part of a chemotherapy medication to cancer
victims. We keep feeding the person these molecules (and yes, it makes the
person weak and sick, because the molecules cause garbage to accumulate in all
the cells in the body) until the cancer cells are all dead. Then we stop
feeding the person the molecules, and let their body gradually recover, their
hair grow back, etc. If all goes well, the result is that we've cured the
person of their cancer.
Imagine all that coming from the use
of your spare CPU cycles. Pretty nice, huh?