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The authors compute the potential of mean force (PMF) between united-atom methane molecules across varying temperatures and integration time-steps to assess numerical stability in free energy calculations. Compared to an equipartition-preserving 0.5 fs baseline, larger time-steps artificially deepen the contact minimum, introducing spurious stabilization into relative free energy landscapes. Using quasichemical theory, they show this artifact is driven entirely by altered hydrophobic contributions and internal liquid pressure rather than hydrophilic effects.
Standard molecular dynamics time-steps silently exaggerate hydrophobic interactions, corrupting biomolecular association landscapes simply by violating energy equipartition.
Molecular dynamics simulations are used to compute the potential of mean force (PMF) between two united-atom methane molecules at several temperatures and integration time-steps. At a fixed time-step, the contact minimum of the PMF deepens with increasing temperature, as expected for hydrophobicity driven association. Compared with a time-step of 0.5 fs, one that preserves equipartition, larger time-steps alter the PMF and make the contact minimum more favorable. Thus even relative free energy values are sensitive to time-steps that break equipartition. Using quasichemical theory, we partition the free energy of association into hydrophobic and hydrophilic contributions. The hydrophilic contribution opposes association and is insensitive to the time-step. Thus the artificial enhancement of association at larger time-steps comes entirely from the hydrophobic contribution. We explain this behavior through the temperature dependence of the internal pressure of the liquid. The same analysis also accounts for earlier observations of the liquid's p-V behavior under conditions that break equipartition.