Insights from Free Energy Calculations: Protein Conformational Equilibrium, Driving Forces and Ligand Binding Processes
Accurately calculating ligand-protein binding affinity has practical applications in computeraided ligand design, but it is still challenging in computational chemistry. In this presentation, I will discuss using the M2 method to compute the binding affinities of various types of inhibitors to p38α MAP kinase. The method is an endpoint approach that uses an empirical force field and implicit solvent models to find stable conformations in the free and bound states of a system and then compute the free energy of each species. Notably, some analogs do not have ligand-p38 co-crystal structures. Our computed binding free energies yield excellent agreement with experimental data and reveal the driving forces of binding. Our results also suggest the dynamic equilibrium between different protein conformations.
In addition, I will introduce a novel computational approach, Hopping Minima, for the determination of conformational transitions of single molecules as well as binding pathways for molecular complexes. The method begins by thoroughly sampling a set of conformational minima for a molecular system. The natural motions of the system are modeled using the normal modes of the sampled minima and multiple minima are finally combined to form binding pathways for molecular complexes. We will discuss our model systems, a set of chemical host−guest systems: two cryptophane hosts with two guest cations, trimethylammonium and tetramethylammonium. I will also discuss the energetic information along a binding pathway.
Physical Chemistry Seminar Series
Prof. Rigoberto Hernandez (404-894-0594)