Binding free energy landscape of c-Src kinase to its inhibitors sampled by molecular dynamics simulations: Effect of ligand size and flexibility

Protein kinases (PKs) play important roles in cellular signal transduction. Their dysfunction leads to disease such as cancer thus they are considered attractive drug targets. To design a selective PK inhibitor, we must elucidate the regulatory mechanism at the atomic level, which is difficult to obtain solely by experiments. We performed extensive molecular dynamics (MD) simulations to sample the binding free energy landscapes of c-Src kinase to its inhibitors of varying sizes and flexibilities. We used replica exchange MD simulations in two-dimensions to significantly enhance the sampling of the protein-ligand conformational space. We collected over 600 microseconds of trajectory data from which we obtained multiple un/binding events, obtained the structures of bound, intermediate and encounter poses and characterized the binding pathways. In addition, we investigated the effect of ligand size and flexibility on the binding mechanism and discuss possible implications on drug design.