Solid-State NMR\nValidation of OPLS4: Structure of\nPC-Lipid Bilayers and Its Modulation by Dehydration

Atomistic molecular dynamics (MD) simulations are a much-used\ntool\nfor investigating the structure and dynamics of biomembranes with\natomic resolution. The validity of the representations obtained is\ndetermined by the accuracy and realism of the MD model (force field).\nHere, we evaluated the proprietary OPLS4 force field of Schrödinger,\nInc. against atomic-resolution experimental data, and compared its\nperformance to CHARMM36, one of the best-performing openly available\nforce fields. As a benchmark, we used high-resolution nuclear magnetic\nresonance (NMR) order parameters for C–H bondsdirectly\nand reliably calculable from MD simulationsmeasured in phosphatidylcholine\n(PC) lipid bilayers under varying hydration conditions. Comparisons\nwere made with two dehydration data sets: for saturated (1,2-dimyristoylphosphatidylcholine,\nDMPC) lipid bilayers from the literature and for unsaturated (1-palmitoyl-2-oleoylphosphatidylcholine,\nPOPC) lipid bilayers measured here. Our findings indicate that OPLS4\nreproduces the structure and dehydration response of PC-lipid bilayers\nfairly well, even slightly outperforming CHARMM36. Both models’\nmain inaccuracies appear in (1) the order parameter magnitudes in\nthe glycerol backbone and unsaturated carbon segments and (2) the\nqualitatively differing structural response of the PC headgroup to\ndehydration compared to experiments. In summary, this work underscores\nthe importance of independent validation for (proprietary) force fields\nand highlights the striking similarities and nuanced differences between\nOPLS4 and CHARMM36 in describing biomembranes.