Molecular dynamics simulations of cholesterol-rich membranes using a coarse-grained force field for cyclic alkanes

Abstract

The architecture of a biological membrane hinges upon the fundamental fact that its properties are determined by more than the sum of its individual components. Studies on model membranes have shown the need to characterize in molecular detail how properties such as thickness, fluidity, and macroscopic bending rigidity are regulated by the interactions between individual molecules in a non-trivial fashion. Simulation-based approaches are invaluable to this purpose but are typically limited to short sampling times and model systems that are often smaller than the required properties. To alleviate both limitations, the use of coarse-grained (CG) models is nowadays an established computational strategy. We here present a new CG force field for cholesterol, which was developed by using measured properties of small molecules, and can be used in combination with our previously developed force field for phospholipids. The new model performs with precision comparable to atomistic force fields in predicting the properties of cholesterol-rich phospholipid bilayers, including area per lipid, bilayer thickness, tail order parameter, increase in bending rigidity, and propensity to form liquid-ordered domains in ternary mixtures. We suggest the use of this model to quantify the impact of cholesterol on macroscopic properties and on microscopic phenomena involving localization and trafficking of lipids and proteins on cellular membranes.

Computer simulations of protein–membrane systems

“…419 In their simulation setups featuring only lipids, i.e., in the absence of proteins they employed the SDK model. 92 , [420][421][422] The SDK model is a CG-FF originally developed by Shinoda, DeVane, and Klein (SDK), which has been demonstrated to correctly model the interfacial interaction of lipids and water. 92,93,423 This model was also shown to reliably reproduce the energy barrier for diacylglycerol-water flip-flop and interfacial tensions.…”

Lipid droplet biogenesis is driven by liquid-liquid phase separation

“…The MD simulations containing only lipids were performed using the software LAMMPS 30 and employing the Shinoda-Devane-Klein (SDK) force field [31][32][33][34] . Combination rules, as described in 35 , were used to derive non-bonded interactions of DAG with DOPE and cholesterol. Initial configurations and input files were obtained through conversion of atomistic snapshots using the CG-it software (https://github.com/CG-it/).…”

Coexistence of lipid phases stabilizes interstitial water in the outer layer of mammalian skin

“…Atomistic simulation parameters were taken from the CHARMM36 force field (Klauda et al, 2010;Venable et al, 2014) for all lipids, CGENFF (Vanommeslaeghe et al, 2010) for small molecules and TIP3P (Jorgensen et al, 1983) for water. CG force field parameters for acyl chains, ester groups, hydroxyl groups, cholesterol and water are from published work (MacDermaid et al, 2015;Shinoda et al, 2010). Parameters for amides and the protonated carboxyl group were also derived from experimental properties of the corresponding liquids (see Supplementary Methods).…”

“…The programs NAMD (Phillips et al, 2005) and LAMMPS (Plimpton, 1995) were employed to carry out MD simulations at the atomic and CG resolutions, respectively. The protocols to treat non-bonded interactions and pressure and temperature coupling are as previously used (MacDermaid et al, 2015) when treating atomistic and CG bilayers. Unless otherwise noted, simulations were carried out at a target temperature of 30 °C and pressure of 1 atm; integration steps were 2 fs and 10 fs for atomistic and CG simulations, respectively.…”