The lag between the Hamiltonian and the system configuration in free energy perturbation calculations

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Abstract
The energetic response of two test systems to changes in the governing Hamiltonians (empirical potential energy functions) are examined. For these two systems—neon in water using periodic boundary conditions and partially solvated trypsin—a systematic lag is observed between changes in the Hamiltonian and changes in a component of the energetic trajectory which is relevant to free energy perturbation (FEP) calculations. This observation appears inconsistent with one of the underlying assumptions of a commonly used implementation of FEP simulations: ‘‘slow growth’’ or ‘‘thermodynamic integration.’’ The calculations presented here suggest that the relevant component of the system energetics lags the Hamiltonian by a minimum of about 0.6 ps. Implications of this lag for designing reliable methodologies to use with various implementations of FEP calculations are discussed.

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