Molecular Dynamics Simulations and Free Energy Calculations of a Novel Series of Protein Tyrosine Phosphatase 1B Difluoromethylenephosphonic Acid Inhibitors

Abstract

Binding models for a series of difluoromethylenephosphonic (DFMP) and difluoromethylenesulfonic (DFMS) acids to protein tyrosine phosphatase 1B (PTP1B) were studied by molecular docking,molecular dynamics (MD) simulations,and free energy calculations. Binding free energies were computed using the molecular mechanics/ generalized Born surface area (MM/GBSA) methodology based on 1 ns MD simulations. The order of affinities for the studied inhibitors can be accurately predicted using previously predicted binding free energies. Inhibitor/residue interaction profiles for all inhibitors were systematically generated using MM/GBSA free energy decomposition analysis. Inhibitor/residue interaction profiles demonstrated that electrostatic interactions between the negative charge center of DFMP/DFMS groups and Arg221 of PTP1B are a crucial part of the studied molecule affinities. Furthermore,the fluorine atom or other hydrogen bonding donor atoms with appropriate radii will improve inhibitor binding to the primary binding site of PTP1B.