Developing CHARMM-Compatible Lipid Parameters for Ceramides and United Atom Chains

Abstract

Biological membranes form a barrier to protect the cell from its environment and consist of a wide variety of lipids. In molecular simulations, accurate force field (FF) parameters are crucial for representing biological membranes. Although all-atom FFs, such as CHARMM36 (C36), can now accurately represent a variety of lipid chains (saturated, unsaturated, and branched) and head groups (PC, PE, PG, and PS), parameters for ceramide lipids are lacking. These lipids are common in biology (neuronal and ocular lens membranes) and are involved in lipid domain formation with cholesterol. Quantum mechanical calculations are used to develop torsional profiles and partial charges of the head group. Molecular dynamics (MD) simulations of palmitoylsphingomyelin (PSM) are used to test new parameters in comparison with available deuterium order parameters. The goal of this new lipid parameter set is to obtain the proper phase of PSM as a function of temperature, where previous models have failed. The development of a CHARMM-compatible united atom (UA) chain model will also be presented, referred to here as C36-UA. This is an extension of previous work (Hénin et al. JPC, 112: 7008 (2008)) to the C36 FF. MD simulations of pure and mixed bilayers with cholesterol demonstrate a UA-chain model that is accurate and compatible with the CHARMM family of force fields. MD simulations of micelle formation of short-chain lipids and single-chained detergents are used to demonstrate the ability of C36-UA to self-assemble lipids. MD simulations with C36-UA allow for timescales not approachable with all-atom models without a loss of accuracy, which may have applications to lipid organization and studies with membrane-associated proteins.