Effects of Biomolecular Flexibility on Alchemical Calculations of Absolute Binding Free Energies

摘要

The independent trajectory thermodynamic integration (IT-TI) approach (Lawrenz, M., et al. J. Chem. Theory. Comput 2009, 5, 1106-1116) for free energy calculations with distributed computing is employed to study two distinct cases of protein-ligand binding: first, the influenza surface protein Nl neuraminidase bound to the inhibitor oseltamivir, and second, the Mycobacterium tuberculosis enzyme RmlC complexed with the molecule CID 77074. For both systems, finite molecular dynamics (MD) sampling and varied molecular flexibility give rise to IT-TI free energy distributions that are remarkably centered on the target experimental values, with a spread directly related to protein, ligand, and solvent dynamics. Using over 2 {is of total MD simulation, alternative protocols for the practical, general implementation of IT-TI are investigated, including the optimal use of distributed computing, the total number of alchemical intermediates, and the procedure to perturb electrostatics and van der Waals interactions. Aprotocol that maximizes predictive power and computational efficiency is proposed. IT-TI outperforms traditional TI predictions and allows a straightforward evaluation of the reliability of free energy estimates. Our study has broad implications for the use of distributed computing in free energy calculations of macromolecular systems.