Quantitative Comparison Against Experiments Reveals Imperfections in Force Fields' Descriptions of Phospholipid-Cholesterol Interactions

Cholesterol is a central building block in biomembranes, where it induces orientational order, slows down diffusion, renders the membrane stiffer, and drives domain formation. Molecular dynamics (MD) simulations have played a crucial role in resolving these effects at the molecular level, yet it has recently become evident that different MD force fields predict quantitatively different behavior. Although easily neglected, identifying such limitations is increasingly important as the field rapidly progresses towards simulations of complex membranes mimicking the in vivo conditions: Pertinent multi-component simulations must capture accurately the interactions between their fundamental building blocks, such as phospholipids and cholesterol. Here, we define quantitative quality measures for simulations of binary lipid mixtures in membranes against the C-H bond order parameters and lateral diffusion coefficients from NMR spectroscopy as well as the form factors from X-ray scattering. Based on these measures, we perform a systematic evaluation on the ability of commonly used force fields to describe the structure and dynamics of binary mixtures of phosphatidylcholine and cholesterol. None of the tested force fields clearly outperforms the others across the tested properties and conditions, but the Slipids parameters provide the best overall performance. The quality-evaluation metrics introduced in this work will, particularly, foster future force field development and refinement for multi-component membranes using automated approaches.