Protein-protein interfaces (PPI) that play key roles in multiple cellular signaling pathways have been recognized as important drug targets. However, many have flexible, shallow binding sites that exhibit substantial structural rearrangement upon ligand binding. This makes rational design of PPI inhibitors very difficult. Recent advances in enhanced sampling molecular dynamics (MD) and free energy perturbation (FEP) techniques, coupled with the availability of high performance graphical processing unit (GPU) hardware, allow us to probe protein-ligand interactions on an atomistic level, while taking full account of protein flexibility, ligand conformational rearrangements and solvation effects. Here we present MD and FEP studies of inhibition of PPIs by macrocyclic stapled peptides, small molecule ligands and antibodies. In addition to predicting binding free energies in good agreement with experimental results, our simulations reveal structural and dynamic features which enhance binding for each class of ligands studied, and provide insight into the design of more potent PPI inhibitors.

Study of protein-protein interface inhibition through molecular dynamics and free energy simulations: Application to staple peptides, small molecules, and antibodies

248th National Meeting (2014)

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