Capturing Phase Behavior of Ternary Lipid Mixtures with a Refined Martini Coarse-Grained Force Field

Abstract

Whether lipid rafts are present in the membranes of living cells remains hotly disputed despite their incontrovertible existence in liposomes at 298 K. In attempts to resolve this debate, molecular dynamics (MD) simulations have been extensively used to study lipid phase separation at high resolution. However, computation has been of limited utility in this respect because the experimental distributions of phases in lamellar lipid mixtures are poorly reproduced by simulations. In particular, all-atom (AA) approaches suffer from restrictions on accessible time scales and system sizes whereas the more efficient coarse-grained (CG) force fields remain insufficiently accurate to achieve correspondence with experiment. In this work, we refine the CG Martini parameters for the high- and low-melting temperature (T m) lipids 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). Our approach involves the modification of bonded Martini parameters based on fitting to atomistic simulations conducted with the CHARMM36 lipid force field. The resulting CG parameters reproduce experimental structural and thermodynamic properties of homogeneous lipid membranes while concurrently improving simulation fidelity to experimental phase diagrams of DPPC, DOPC, and cholesterol lipid mixtures. Importantly, the refined parameters provide much better phase accuracy for regions near the critical point that mimic the lipid concentrations under physiological conditions.

Unsupervised Machine Learning for Analysis of Coexisting Lipid Phases and Domain Growth in Biological Membranes

“…Contrary to the Updated force field, the lipid mixture based on the Standard Martini force field does not show any tendency for phase separation or domain formation(Fig. 2B, bottompanel), in agreement with previously published data52 .…”

“…This lipid ratio has been experimentally and computationally observed to transitioning towards a phase separated Liquidordered/Liquid-disordered state 54,56 . The lipids were represented using the Martini V2.2 force field 39 with a refined set of parameters, which has shown an improved phase separation behavior 52 . Similarly, simulation with the standard Martini lipid model was also carried on.…”

Twisting and tilting of a mechanosensitive molecular probe detects order in membranes

“…The DOB-phase classification introduced for the analysis of ternary mixture membranes was used to distinguish lipid order in different regions of complex membranes by using the twist angle histograms as a differentiation criterion. In most MD simulations, the determination of lipid phases and the detection of nanoscopic domains rely on involved calculations and analyses, such as the calculation of deuterium order parameters, estimation of cumulative radial distribution functions 86 or the use of sophisticated hidden Markov models. 78 Besides being computationally demanding, these approaches may be sensitive to undulations and distortions of membranes, which can affect the accuracy of the calculation and introduce errors.…”

“…Due to the slow diffusion of lipids and the microsecond timescale required to form lipid domains, most of MD studies involving simulations of lipid nanodomains employ coarsegrained models, 20,[86][87][88][89][90][91] although few studies using all-atom simulations can be found in the literature. 78,79,[92][93][94][95] Here, we retain the atomic-level resolution of Flipper-TR as its working mechanism may not be accurately represented by a coarsegrained model.…”

Martini Coarse-Grained Model of Hyaluronic Acid for the Structural Change of Its Gel in the Presence of Monovalent and Divalent Salts

“…Continuous efforts for developing transferable Martini models have been reported for several molecules, including polyethylene oxide (PEO) [ 31 ], polyethers [ 32 ], perfluorosulfonic acid polymer membranes [ 33 ], and methacrylate-based copolymers [ 34 ]. Martini models have also been successful in studies capturing the phase behavior and phase transitions of several polymer systems [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. The above examples justify the wide acceptability of Martini CG models for various compounds and polymer systems.…”