Probing the Effect of Conformational Constraints on Binding

Increasing the strength of binding between a molecule and a receptor is an important technique in the design of effective drugs. One experimental technique to increase the strength of binding (called "binding affinity") is to synthesize molecules that are already in the shape that it will take when bound to a receptor. This technique works because it decreases the binding entropy which increases the overall binding affinity. A recent experimental study of a series of receptor-molecule complexes (the Grb2 SH2 domain with peptide analogues) aimed to increase the binding affinity by introducing a bond constraint. However, the constrained molecules had less favorable binding entropies than their flexible counterparts. Yue Shi of the Ren lab at UT Austin aimed to probe the origin of this entropy paradox with molecular dynamics simulations which were run on Lonestar and Ranger at TACC. Their group used approximately 2 million CPU hours on Ranger and almost 1 million on Lonestar this past year. Their research addresses biological and medical challenges from single molecules to the genome with high performance computing and theory. In collaboration with other experimental groups, they utilize computer modeling and simulations to understand these complex biomolecular systems and to discover molecules for treating disease and improving human health. Effectively communicating the results of their computational studies to experimentalists is essential to the success of their collaborative efforts. Anne Bowen of the Texas Advanced Computing Center collaborated with Yue Shi to prepare animations and graphics to better explain the origins of the "entropy paradox" to experimentalists and the general public.} % end of abstract