A High-Throughput Steered Molecular Dynamics Study on the Free Energy Profile of Ion Permeation through Gramicidin A

TL;DR

This study uses high-throughput steered molecular dynamics to analyze the free energy profile of potassium ion permeation through Gramicidin A, highlighting the importance of extensive sampling for accurate estimates.

Contribution

It demonstrates the application of large-scale SMD simulations with 2000 pulls to evaluate free energy profiles and discusses the impact of sampling and permeation pathways on accuracy.

Findings

Work distributions are non-Gaussian at high pulling speeds.

Statistical errors remain significant despite extensive sampling.

Different permeation pathways influence free energy estimates.

Abstract

Steered molecular dynamics (SMD) simulations for the calculation of free energies are well suited for high-throughput molecular simulations on a distributed infrastructure due to the simplicity of the setup and parallel granularity of the runs. However, so far, the computational cost limited the estimation of the free energy typically over just a few pullings, thus impeding the evaluation of statistical uncertainties involved. In this work, we performed two thousand pulls for the permeation of a potassium ion in the gramicidin A pore by all-atom molecular dynamics in order to assess the bidirectional SMD protocol with a proper amount of sampling. The estimated free energy profile still shows a statistical error of several kcal/mol, while the work distributions are estimated to be non-Gaussian at pulling speeds of 10 {\AA}/ns. We discuss the methodology and the confidence intervals in relation to increasing amounts of computed trajectories and how different permeation pathways for the potassium ion, knock-on and sideways, affect the sampling and the free energy estimation.