BPS2026 – Phosphatidylserine potential energy function for C36, C36/LJ-PME, and the drude polarizable model

The CHARMM36 (C36) pairwise additive lipid forcefield (FF) and the Drude polarizable FF have been modified for inclusion of long-range Lennard-Jones (LJ) interactions, termed C36/LJ-PME and Drude2023, respectively. While the force fields show good agreement with experiment for zwitterionic lipids, molecular dynamics studies using these models are limited by a deficiency of lipid types available. In this work, we are expanding the available lipids in C36/LJ-PME and Drude2023 to include phosphatidylserine (PS). Furthermore, we improve the accuracy of PS lipids in simulations of C36 without the use of long-range LJ. A pairwise exception to the Lorentz-Berthelot combining rules, known as an NBFIX, is parametrized from osmotic pressure calculations of glycine to reduce the attraction between amine and acetate chemical groups. This change leads to a reduction of PS headgroup-headgroup binding and better agreement with both scattering experiments and NMR order parameters. The changes to the linker region parameters of zwitterionic lipids for C36/LJ-PME are transferable to PS lipids, which further improves agreement with experiment, especially monolayer pressure-area isotherms. Parametrization of the Drude polarizable model includes NBFIX changes and Thole screening factors (NBTHOLE) between atom types and dihedral scans of the headgroup. Simulations using the Drude model with the new SWM4-HLJ water model show good agreement with experiment. The improved agreement of the pairwise additive models and the addition of PS lipids for the Drude polarizable models will prove valuable for future membrane simulation studies containing this biologically important lipid.