Guest post from Dr. Gregory Bowman, UC Berkeley
Most rational drug design efforts assume the target protein exists in a single structure and that the structure of one region of the protein--called the active site--allows the protein to perform some function. Once this assumption is made, the only way to manipulate a protein’s activity is with inhibitors that bind the active site tightly enough to block it from performing its intended function. Unfortunately, this strategy only works for ~15% of proteins, greatly limiting the number of proteins we can manipulate for therapeutic purposes.
In a recent article published in the Proceedings of the National Academy of Sciences (link), I showed that simulations run on Folding@home can reveal new ways of manipulating a protein's activity. Specifically, I start off by recognizing that proteins are actually flexible and then use Folding@home to enumerate the different conformations a protein adopts. I then use statistical analysis to find parts of the protein that can communicate with the active site through a process called allostery. These regions--called allosteric sites--are attractive drug targets as the binding of small molecules to them can be communicated to the active site, ultimately affecting activity.
As a proof of principle, I showed that my approach can identify a known allosteric site in Beta-lactamase (see figure below). This protein is an important drug target because it can confer bacteria with antibiotic resistance by breaking down antibiotics like penicillin. I also use my approach to predict new allosteric sites in Beta-lactamase and two other proteins that play important roles in immune deficiencies and HIV. Now I'm performing experiments to test my predictions. It will require a lot more of your WUs, but I hope this type of approach can eventually lead to new pharmaceuticals.
On the left is a structure of Beta-lactamase that most people would think of as the structure of this protein. However, the right shows a different structure with a drug (cyan) bound in a pocket that isn’t visible in the structure on the left. Binding of this drug somehow affects the structure near the active site (green). Using my approach, I’m able to start with the structure on the left and then predict the existence of the structure on the right and the allosteric site the drug is bound to.