Efficient calculation of the free energy for protein partitioning using restraining potentials

An approach for the efficient simulation of phase-separated lipid bilayers, for use in the calculation of equilibrium free energies of partitioning between lipid domains, is proposed. The methodology exploits restraint potentials and rectangular aspect ratios that enforce lipid phase separation, allowing for the simulation of smaller systems that approximately reproduce bulk behavior. The utility of this approach is demonstrated through the calculation of potentials of mean force for the translation of a transmembrane protein between lipid domains. The impact of the imposed restraints on lipid tail ordering and lipid packing are explored, providing insight into how restraints can best be employed to compute accurate free-energy surfaces. This approach should be useful in the accurate calculation of equilibrium partition coefficients for transmembrane protein partitioning in heterogeneous membranes, providing insight into the thermodynamic driving forces that control this fundamental biophysical

Automated summary

An efficient simulation method for phase-separated lipid bilayers is proposed for calculating equilibrium free energies of partitioning between lipid domains. The approach utilizes restraint potentials and rectangular aspect ratios to enforce lipid phase separation and mimic bulk behavior in smaller systems. The utility of the method is demonstrated by calculating potentials of mean force for transmembrane protein translation. The impact of restraints on lipid properties is explored to improve the accuracy of free-energy surfaces.