Relative Binding Enthalpies from Molecular Dynamics Simulations Using a Direct Method

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• 作者：Amitava Roy ; Duy P. Hua ; Joshua M. Ward ; Carol Beth Post
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2014
• 出版时间：July 8, 2014
• 年：2014
• 卷：10
• 期：7
• 页码：2759-2768
• 全文大小：483K
• ISSN：1549-9626

文摘

The potential for reliably predicting relative binding enthalpies, 螖螖E, from a direct method utilizing molecular dynamics is examined for a system of three phosphotyrosyl peptides binding to a protein receptor, the Src SH2 domain. The binding enthalpies were calculated from the potential energy differences between the bound and the unbound end-states of each peptide from equilibrium simulations in explicit water. The statistical uncertainties in the ensemble-mean energy values from multiple, independent simulations were obtained using a bootstrap method. Simulations were initiated with different starting coordinates as well as different velocities. Statistical uncertainties in 螖螖E are 2 to 3 kcal/mol based on calculations from 40, 10 ns trajectories for each system (three SH2鈥損eptide complexes or unbound peptides). Uncertainties in relative component energies, comprising solute鈥搒olute, solute鈥搒olvent and solvent鈥搒olvent interactions, are considerably larger. Energy values were estimated from an unweighted ensemble averaging of multiple trajectories with the a priori assumption that all trajectories are equally likely. Distributions in energy鈥搑msd space indicate that the trajectories sample the same basin and the difference in mean energy values between trajectories is due to sampling of alternative local regions of this superbasin. The direct estimate of relative binding enthalpies is concluded to be a reasonable approach for well-ordered systems with 螖螖E values greater than 3 kcal/mol, although the approach would benefit from future work to determine properly distributed starting points that would enable efficient sampling of conformational space using multiple trajectories.