Single molecule pulling with large time steps

TL;DR

This paper demonstrates that large time step molecular dynamics simulations can accurately determine free energy differences in biomolecular unfolding, significantly improving computational efficiency while maintaining theoretical correctness.

Contribution

It extends the Jarzynski theorem to large time step trajectories and validates this approach for complex biomolecules like deca-alanine.

Findings

Large time steps (up to 3.2 fs) produce accurate free energy estimates.

The method is practical for complex biomolecules in force spectroscopy.

Large steps increase efficiency despite unphysical trajectory artifacts.

Abstract

Recently, we presented a generalisation of the Jarzynski non-equilibrium work theorem for phase space mappings. The formalism shows that one can determine free energy differences from approximate trajectories obtained from molecular dynamics simulations in which very large timesteps are used. In this work we test the method by simulating the force induced unfolding of a deca-alanine helix in vacuum. The excellent agreement between results obtained with a small, conservative time step of 0.5 fs and results obtained with a time step of 3.2 fs (i.e., close to the stability limit) indicates that the large time step approach is practical for such complex biomolecules. We further adapt the method of Hummer and Szabo for the simulation of single-molecule force spectroscopy experiments to the large time step method. While trajectories generated with large steps are approximate and may be unphysical - in the simulations presented here we observe a violation of the equipartition theorem - the computed free energies are exact in principle. In terms of efficiency, the optimum time step for the unfolding simulations lies in the range 1-3 fs.