Solvent Interaction Energy Calculations on Molecular Dynamics Trajectories: Increasing the Efficiency Using Systematic Frame Selection

Abstract

End-point methods such as linear interaction energy (LIE) analysis, molecular mechanics generalized Born solvent-accessible surface (MM/GBSA), and solvent interaction energy (SIE) analysis have become popular techniques to calculate the free energy associated with protein–ligand binding. Such methods typically use molecular dynamics (MD) simulations to generate an ensemble of protein structures that encompasses the bound and unbound states. The energy evaluation method (LIE, MM/GBSA, or SIE) is subsequently used to calculate the energy of each member of the ensemble, thus providing an estimate of the average free energy difference between the bound and unbound states. The workflow requiring both MD simulation and energy calculation for each frame and each trajectory proves to be computationally expensive. In an attempt to reduce the high computational cost associated with end-point methods, we study several methods by which frames may be intelligently selected from the MD simulation including clustering and address the question of how the number of selected frames influences the accuracy of the SIE calculations.