(515a) Effects of Single Atom Modifications on Protein-Ligand Interactions Studied Using Markov State Modeling

In protein-ligand interaction studies, it is often observed that small changes in the structure of ligands can have a large influence on their binding affinities on proteins. For example, recent experimental studies of ligand binding on glycogen synthase kinase -3 (GSK-3) have shown that changing the position of nitrogen on the pyridine ring of ligands has a dramatic effect on their inhibition efficiency. In this work, we have implemented Markov State Modeling in molecular dynamics simulations to study if one can discern the influence of these small changes in the ligand structure on their binding affinity on GSK-3 protein. We find that our modeling is able to capture the effect of single atom modifications on the binding energy as well as provide insights into the underlying reasons for this observation.