Peptide Gaussian Accelerated Molecular Dynamics (Pep-GaMD) Enhanced Sampling and Free Energy and Kinetics Calculations of Peptide Binding

Abstract

Peptides mediate up to 40% of known protein-protein interactions in higher eukaryotes and play an important role in cellular signaling. However, it is challenging to simulate both binding and unbinding of peptides through conventional molecular dynamics (cMD), due to long biological timescales and extremely high flexibility of the peptides. Based on the Gaussian accelerated molecular dynamics (GaMD) enhanced sampling technique, we have developed a new computational method “Pep-GaMD”, which selectively boosts essential potential energy of the peptide in order to effectively model its high flexibility. Pep-GaMD has been demonstrated on binding of model peptides to target proteins. Independent microseconds-time-scale Pep-GaMD simulations have captured repetitive peptide dissociation and binding events, which enable us to calculate peptide binding thermodynamics and kinetics. The calculated binding free energies and kinetic rate constants agreed very well with available experimental data. Thus, Pep-GaMD provides a highly efficient, easy-to-use approach for unconstrained enhanced sampling and calculations of peptide binding free energies and kinetics.