Investigating Lipid Phase Changes from Liquid Crystalline to Ripple to Gel Phases with All-Atom Molecular Dynamics Simulations

Abstract

Lipid mixed with water can exist in many different phases that depends on various factors, such as hydration, temperature and pressure (J. Chem. Theory Comput.,6 (8): 2488 (2010)). The liquid crystalline (chain-disordered state) is a well-studied phase for single lipid bilayers both experimentally and computationally. At low enough temperatures or hydration levels, this chain-disordered state can change to a gel state with high chain order and a certain chain tilt with respect to the membrane normal. Depending on the lipid, an intermediate phase can exist between the gel and liquid crystalline phase, which is known as the ripple phase. The main objective of this study was probing the accuracy of the CHARMM36 (C36) force field (FF) (J. Phys. Chem. B.,114 (23): 7830 (2010)) in predicting phase changes in lipid bilayers. Pure and mixed lipid bilayers at different compositions of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and dipalmitoylphosphatidylcholine (DPPC) were studied using molecular dynamics (MD) simulations. Based on the pure gel-phase transition temperature of each lipid, a range of temperatures was selected (from 200C to 400C) (Biochem. 18: 3280 (1979)). MD simulations were able to capture ripple phase in %25 DMPC and %75 DPPC mixture and pure DMPC at 250C. Simulations were run for 200-300 ns. MD simulations also show either a gel state or gel-like state depending on if the system gets trapped (gel-like is a state without proper leaflet alignment). Phase diagram was compared to that obtained from experimental data such as NMR. Based on the phase diagram and our transition temperatures, C36 FF accurately predicts the phase transitions of this fully saturated PC lipids. Therefore, studies on phase coexistence of liquid ordered and liquid disordered domains are likely to be accurate using the C36 FF.