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

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.
Comment: This document is the Accepted Manuscript version of a Published Work that appeared in final form in J. Chem. Theory Comput., copyright 2011 after peer review and technical editing by the publisher. To access the final edited and published work see doi:10.1021/ct100707s