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Understanding how different classes of molecules move across biologicalmembranes is a prerequisite to predicting a solute's permeation rate, which isa critical factor in the fields of drug design and pharmacology. We use biasedMolecular Dynamics computer simulations to calculate and compare the freeenergy profiles of translocation of several small molecules across1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid bilayers as a first steptowards determining the most efficient method for free energy calculations. Westudy the translocation of arginine, a sodium ion, alanine, and a single watermolecule using the Metadynamics, Umbrella Sampling, and Replica ExchangeUmbrella Sampling techniques. Within the fixed lengths of our simulations, wefind that all methods produce similar results for charge-neutral permeants, butnot for polar or positively charged molecules. We identify the long relaxationtimescale of electrostatic interactions between lipid headgroups and the soluteto be the principal cause of this difference, and show that this slow processcan lead to an erroneous dependence of computed free energy profiles on theinitial system configuration. We demonstrate the use of committor analysis tovalidate the proper sampling of the presumed transition state, which in oursimulations is achieved only in replica exchange calculations. Based on theseresults we provide some useful guidance to perform and evaluate free energycalculations of membrane permeation.

Free Energy Calculations of Membrane Permeation: Challenges due to Strong Headgroup-Solute Interactions