Finite-Size Effects in Simulations of Peptide/Lipid Assembly

ABSTRACT: Molecular dynamics simulations are an attractive tool for understanding lipid/peptide self-assembly but can be plagued by inaccuracies when the system sizes are too small. The general guidance from self-assembly simulations of homogeneous micelles is that the total number of surfactants should be three to five times greater than the equilibrium aggregate number of surfactants per micelle. Herein, the heuristic is tested on the more complicated self-assembly of lipids and amphipathic peptides using the Cooke and Martini 3 coarse-grained models. Cooke model simulations with 50 to 1000 lipids and no peptide are dominated by finite-size effects, with usually one aggregate (micelle or nanodisc) containing most of the lipids forming at each system size. Approximately 200 systems of different peptide/lipid (P/L) ratios and sizes of up to 1000 lipids yield a “finite-size phase diagram” for peptide driven self-assembly, including a coexistence region of micelles and discs. Insights from the Cooke model are applied to the assembly of dimyristoylphosphatidylcholine and the ELK-neutral peptide using the Martini 3 model. Systems of 150, 450, and 900 lipids with P/L = 1/6.25 form mixtures of lipid-rich discs that agree in size with experiment and peptide-rich micelles. Only the 150-lipid system shows finite-size effects, which arise from the long-tailed distribution of aggregate sizes. The general rule of three to five times the equilibrium aggregate size remains a practical heuristic for the Cooke and Martini 3 systems investigated here. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00232-022-00255-9.