Relative Binding Enthalpies from Molecular Dynamics Simulations Using a Direct Method

ABSTRACT: The potential for reliably predicting relative binding enthalpies, ΔΔE, 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 ΔΔE are 2 to 3 kcal/mol based on calculations from 40, 10 ns trajectories for each system (three SH2−peptide complexes or unbound peptides). Uncertainties in relative component energies, comprising solute−solute, solute−solvent and solvent−solvent 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