Membrane protein simulations with a united-atom lipid and all-atom protein model:lipid–protein interactions, side chain transfer free energies and model proteins

Abstract

We have reparameterized the dihedral parameters in a commonly used united-atom lipidforce field so that they can be used with the all-atom OPLS force field for proteinsimplemented in the molecular dynamics simulation software GROMACS. Simulations withthis new combination give stable trajectories and sensible behaviour of both lipids andprotein. We have calculated the free energy of transfer of amino acid side chains betweenwater and ‘lipid-cyclohexane’, made of lipid force field methylene groups, as ahydrophobic mimic of the membrane interior, for both the OPLS-AA and a modifiedOPLS-AA force field which gives better hydration free energies under simulationconditions close to those preferred for the lipid force field. The average error is4.3 kJ mol−1 for water–‘lipid-cyclohexane’ compared to3.2 kJ mol−1 for OPLS-AAcyclohexane and 2.4 kJ mol−1 for the modified OPLS-AA water–‘lipid-cyclohexane’. We have also investigated the effectof different methods to combine parameters between the united-atom lipid force field andthe united-atom protein force field ffgmx. In a widely used combination, the strength ofinteractions between hydrocarbon lipid tails and proteins is significantly overestimated,causing a decrease in the area per lipid and an increase in lipid ordering. Using straightcombination rules improves the results. Combined, we suggest that using OPLS-AAtogether with the united-atom lipid force field implemented in GROMACS is areasonable approach to membrane protein simulations. We also suggest that usingpartial volume information and free energies of transfer may help to improve theparameterization of lipid–protein interactions and point out the need for accurateexperimental data to validate and improve force field descriptions of such interactions.