We introduce methods to deal with constraints when post-processing free energy simulations using Bennett’s acceptance ratio or related methods. The primary purpose of employing constraints for these free energy methods is to increase the overlap between ensembles required for accuracy and convergence. The new approach is to calculate the free energy costs of applying or removing constraints as additional explicit steps in the free energy cycle. The new techniques focus on higher frequency constraints and uses both gradients and Hessian estimation. Enthalpy, frequency based entropy, and Jacobian based free energy terms are considered. Although the primary utility of this approach may be in calculating free energies with QM and QM/MM systems, we demonstrate the utility of this method with simple classical systems involving harmonic and anharmonic oscillators, a four-atomic benchmark systems, an alchemical mutation of ethane to methanol, and free energy simulations between alanine and serine.

Correcting for the free energy costs of bond or angle constraints in molecular dynamics simulations

249th National Meeting (2015)

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