Evaluating Coarse-Grained MARTINI Force-Fields for Capturing the Ripple Phase of Lipid Membranes.

Abstract

Phospholipids, which are an integral component of cell membranes, exhibit a rich variety of lamellar phases modulated by temperature and composition. Molecular dynamics (MD) simulations have greatly enhanced our understanding of phospholipid membranes by capturing experimentally observed phases and phase transitions at molecular resolution. However, the ripple (Pβ') membrane phase, observed as an intermediate phase below the main gel-to-liquid crystalline transition with some lipids, has been challenging to capture with MD simulations, both at all-atom and coarse-grained (CG) resolutions. Here, with an aggregate ∼2.5 μs all-atom and ∼122 μs CGMD simulations, we systematically assess the ability of six CG MARTINI 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid and water force-field (FF) variants, parametrized to capture the DPPC gel and fluid phases, for their ability to capture the Pβ' phase, and compared observations with those from an all-atom FF. Upon cooling from the fluid phase to below the phase transition temperature with smaller (380-lipid) and larger (>2200-lipid) MARTINI and all-atom (CHARMM36 FF) DPPC lipid bilayers, we observed that smaller bilayers with both all-atom and MARTINI FFs sampled interdigitated Pβ' and ripple-like states, respectively. However, while all-atom simulations of the larger DPPC membranes exhibited the formation of the Pβ' phase, MARTINI membranes did not sample interdigitated ripple-like states at larger system sizes. We then demonstrated that the ripple-like states in smaller MARTINI membranes were kinetically trapped structures caused by finite size effects rather than being representative of true Pβ' phases. We showed that a MARTINI FF variant that could capture the tilted Lβ' gel phase, a prerequisite for stabilizing the Pβ' phase, was unable to capture the rippled phase upon cooling. Our study reveals that the current MARTINI FFs (including MARTINI3) may require specific reparametrization of the interaction potentials to stabilize lipid interdigitation, a characteristic of the ripple phase.