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

ABSTRACT

Free 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.

KEYWORDS:

• Free energy calculations
• lipid membrane permeation
• molecular dynamics simulations
• precision

Acknowledgments

The authors would like to acknowledge two anonymous reviewers for helpful comments. The calculations were performed on the computing facilities of Calcul Québec and the Centre for Research in Molecular Modeling.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by funding from the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC).