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September 28, 2005
Clamping Down, or Loosening Up?
We medicinal chemists spend our days trying to make small molecules that bind to targets in living systems. Almost all of those targets are proteins of one sort or another, and most of them have binding pockets already built into them, which we're trying to hijack for our own purposes. Molecular modelers try to figure out how these things fit together, but there are still a lot of unknowns in what would seem so basic a process.
I'm willing to bet that most chemists and biologists have a mental picture of a small molecule ligand fitting into a binding site which involves the protein sort of folding down around things - gently biting down on the ligand, as it were. It seems intuitively obvious that a protein's motions would settle down once it complexes with its target molecule.
And like a lot of intuitively obvious things in drug research, that idea appears to be mistaken. There's a recent study in the Journal of Medicinal Chemistry from a group at Michigan that tackles this question in a rigorous manner. They looked through the X-ray crystal structure data banks for proteins that have had high-quality structures determined both with and without small molecules bound in them. After controlling for experimental conditions (the temperature that the X-ray structure was taken at, among other things) and for the way the data were processed, they still had a few dozen closely matched pairs.
What they found was that in most of these structures, at least some of the atoms in and near the binding site are more mobile when there's a ligand bound. At times, the effect was pretty dramatic, with the entire binding site becoming more flexible, weirdly enough. Examples where everything got less mobile were found, but that only happened in a minority of the cases. The proteins the authors studied were scattered across a wide range of structural and functional classes, and there's no reason to think that they hit on an anomalous data set.
So, we're going to have to adjust our mental pictures, and the molecular modelers will have to adjust their simulations. I'd like to know just how many of those in silico models of binding would have predicted this greater flexibility. I fear that the answer is "darn near none of them". We have a long way to go.
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