Lessons learned about steered molecular dynamics simulations and free energy calculations

Chemical Biology & Drug Design
Fernando Martín BoubetaMehrnoosh Arrar

Abstract

The calculation of free energy profiles is central in understanding differential enzymatic activity, for instance, involving chemical reactions that require QM-MM tools, ligand migration, and conformational rearrangements that can be modeled using classical potentials. The use of steered molecular dynamics (sMD) together with the Jarzynski equality is a popular approach in calculating free energy profiles. Here, we first briefly review the application of the Jarzynski equality to sMD simulations, then revisit the so-called stiff-spring approximation and the consequent expectation of Gaussian work distributions and, finally, reiterate the practical utility of the second-order cumulant expansion, as it coincides with the parametric maximum-likelihood estimator in this scenario. We illustrate this procedure using simulations of CO, both in aqueous solution and in a carbon nanotube as a model system for biologically relevant nanoheterogeneous environments. We conclude the use of the second-order cumulant expansion permits the use of faster pulling velocities in sMD simulations, without introducing bias due to large dispersion in the non-equilibrium work distribution.

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Citations

Jul 29, 2021·Physical Chemistry Chemical Physics : PCCP·Eduardo R AlmeidaPriscila V S Z Capriles
Dec 22, 2020·ACS Nano·Vishal Maingi, Paul W K Rothemund
Aug 17, 2020·Journal of Chemical Information and Modeling·W F Drew BennettHelgi I Ingólfsson
Nov 11, 2021·The Journal of Physical Chemistry. B·Sangram PrustySusmita Roy

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