Solid-state-NMR validation of OPLS4: Structure of PC-lipid bilayers and its modulation by dehydration

Atomistic molecular dynamics (MD) simulations are a much-used tool for investigating the structure and dynamics in biomembranes with atomic resolution. The validity of the representations obtained is determined by the accuracy and realism of the MD model (force field). Here, we evaluated the proprietary OPLS4 force field of Schrödinger, Inc. against atomic-resolution experimental data and compared its performance to CHARMM36, one of the best-performing openly available force fields. As benchmark, we used high-resolution Nuclear Magnetic Resonance (NMR) order parameters for C–H bonds—directly and reliably calculable from MD simulations—measured in phosphatidylcholine (PC) lipid bilayers under varying hydra- tion conditions. Comparisons were made with two dehydration datasets: for saturated (1,2- dimyristoylphosphatidylcholine DMPC) lipid bilayers from the literature, and for unsaturated (1-palmitoyl-2-oleoylphosphatidylcholine POPC) lipid bilayers measured here. Our findings indicate that OPLS4 reproduces the structure and dehydration-response of PC-lipid bilayers fairly well, even slightly outperforming CHARMM36. Both models’ main inaccuracies appear in (1) the order parameter magnitudes in the glycerol backbone and unsaturated carbon segments, and (2) the qualitatively differing structural response of the PC-headgroup to dehydration compared to experiments. In summary, the presented work underscores the importance of independent validation for (proprietary) force fields and highlights the strik- ing similarities and nuanced differences between OPLS4 and CHARMM36 in describing biomembranes.