Comparison of Umbrella Sampling and Steered Molecular Dynamics Methods for Computing Free Energy Profiles of Toluene Molecules through Phospholipid Bilayers

In this study, we use Molecular Dynamics (MD) to analyze three different corrections of the Steered Molecular Dynamics (SMD) implementation of Jarzynski's Equality (JE) to calculate the FE change for the translocation of a toluene molecule across a lipid bilayer, and compare the accuracy and computational efficiency of these approaches to the results obtained using Umbrella Sampling (US). We show that when computing the free energy profile of a small molecule across a model membrane, the SMD approach suffers from sampling issues that may be alleviated through the use of a slower pulling velocity, but at the cost of computational efficiency. We deduce that, despite its drawbacks, US remains the more viable approach of the two for computing the free energy (FE) profile.