Biochemistry Seminar: Carlos Simmerling
Wed, Oct 02
12:00 PM — 1:00 PM
Marshak160 Convent Ave
Carlos Simmerling, SUNY Stony Brook, “Enzyme-Inhibitor Dynamics – Insights from Simulations”Many important drug targets are flexible and are known to change conformation when ligands bind, presenting challenges for accurate virtual screening as well as obtaining experimental structural and mechanistic data. Perhaps the most well-characterized example is HIV-1 protease, in which a large conformational change is observed between crystal structures of bound and free enzyme. Furthermore, no direct structural data is available for the open form which is presumed to be required for binding substrate proteins into the active site. Design of inhibitors that overcome resistance would be greatly facilitated by an accurate model of the dynamic behavior of HIV-PR in both the bound and unbound states, along with a deeper insight into the mechanistic events associated with binding of substrates and inhibitors. This seminar will describe the development of simulation models that are used to study HIV-PR and validated against crystallographic and EPR solution data. The work is also extended to gain insight into the behavior of other retroviral proteases. Most recently, we have also extended the work to the study of slow-onset enzyme inhibitors, in which a structural rearrangement is believed to accompany binding. Lack of experimental data for the rearrangement transition state prevents rational optimization of inhibitor binding kinetics. Simulation models can help fill this gap and facilitate development of more potent inhibitors.