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iSoLF is a coarse-grained (CG) model for lipid molecules with the implicit-solvent approximation used in molecular dynamics (MD) simulations of biological membranes. Using the original iSoLF (iSoLFv1), MD simulations of lipid bilayers consisting of either POPC or DPPC and these bilayers, including membrane proteins, can be performed. Here, we improve the original model, explicitly treating the electrostatic interactions between different lipid molecules and adding CG particle types. As a result, the available lipid types increase to 30. To parameterize the potential functions of the new model, we performed all-atom MD simulations of each lipid at three different temperatures using the CHARMM36 force field and the modified TIP3P model. Then, we parameterized both the bonded and non-bonded interactions to fit the area per lipid and the membrane thickness of each lipid bilayer by using the multistate Boltzmann Inversion method. The final model reproduces the area per lipid and the membrane thickness of each lipid bilayer at the three temperatures. We also examined the applicability of the new model, iSoLFv2, to simulate the phase behaviors of mixtures of DOPC and DPPC at different concentrations. The simulation results with iSoLFv2 are consistent with those using Dry Martini and Martini 3, although iSoLFv2 requires much fewer computations. iSoLFv2 has been implemented in the GENESIS MD software and is publicly available., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Biological membranes that play major roles in diverse functions are composed of numerous lipids and proteins, making them an important target for coarse-grained (CG) molecular dynamics (MD) simulations. Recently, we have developed the CG implicit solvent lipid force field (iSoLF) that has a resolution compatible with the widely used Cα protein representation [D. Ugarte La Torre and S. Takada, J. Chem. Phys. 153, 205101 (2020)]. In this study, we extended it and developed a lipid-protein interaction model that allows the combination of the iSoLF and the Cα protein force field, AICG2+. The hydrophobic-hydrophilic interaction is modeled as a modified Lennard-Jones potential in which parameters were tuned partly to reproduce the experimental transfer free energy and partly based on the free energy profile normal to the membrane surface from previous all-atom MD simulations. Then, the obtained lipid-protein interaction is tested for the configuration and placement of transmembrane proteins, water-soluble proteins, and peripheral proteins, showing good agreement with prior knowledge. The interaction is generally applicable and is implemented in the publicly available software, CafeMol.

Biological membranes have been prominent targets for coarse-grained (CG) molecular dynamics simulations. While minimal CG lipid models with three beads per lipid and quantitative CG lipid models with >10 beads per lipid have been well studied, in between them, CG lipid models with a compatible resolution to residue-level CG protein models are much less developed. Here, we extended a previously developed three-bead lipid model into a five-bead model and parameterized it for two phospholipids, POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine). The developed model, iSoLF, reproduced the area per lipid, hydrophobic thickness, and phase behaviors of the target phospholipid bilayer membranes at the physiological temperature. The model POPC and DPPC membranes were in liquid and gel phases, respectively, in accordance with experiments. We further examined the spontaneous formation of a membrane bilayer, the temperature dependence of physical properties, the vesicle dynamics, and the POPC/DPPC two-component membrane dynamics of the CG lipid model, showing some promise. Once combined with standard Cα protein models, the iSoLF model will be a powerful tool to simulate large biological membrane systems made of lipids and proteins.