Accuracy and precision of simulated free energies: water permeation of hydrated DPPC bilayers as a paradigm

Abstract

ABSTRACTFree energies play a determining role in the transmembrane permeability of lipid bilayers to small molecules. The precision of the calculated free energies, in particular, can seriously affect the reliability of simulations of permeation events. Free energy profiles are evaluated with different known techniques for a water molecule inside a hydrated bilayer in order to assess the accuracy and precision of free energy calculations as well as the associated computational cost within the popular Groningen Machine for Chemical Simulations (GROMACS) software package. The different computational approaches employed include the method of constrained particles, umbrella sampling and thermodynamic integration. When free energy profiles computed from MD trajectories of similar timescales are compared, umbrella sampling is found to afford the best precision among the methods investigated, albeit at the expense of computational effort.