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Title: 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. 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.

Authors:
ORCiD logo [1]; ORCiD logo [2];  [2];  [3];  [1];  [4];  [1];  [2]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Biosciences and Biotechnology Division. Physical and Life Sciences Directorate
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Georgetown Univ., Washington, DC (United States). Biochemistry and Molecular Biology Dept.
  4. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Applications, Simulations, and Quality Division. Computation Directorate
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC). Advanced Scientific Computing Research (ASCR) (SC-21); LANL Laboratory Directed Research and Development (LDRD) Program; National Inst. of Health (NIH) (United States)
OSTI Identifier:
1512613
Alternate Identifier(s):
OSTI ID: 1526950
Report Number(s):
LLNL-JRNL-750994; LA-UR-18-23792
Journal ID: ISSN 1549-9618; 936287
Grant/Contract Number:  
AC52-07NA27344; AC52-06NA25396; AC05-00OR22725; HHSN261200800001E; 89233218CNA000001
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Chemical Theory and Computation
Additional Journal Information:
Journal Volume: 14; Journal Issue: 11; Journal ID: ISSN 1549-9618
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science

Citation Formats

Carpenter, Timothy S., López, Cesar A., Neale, Chris, Montour, Cameron, Ingólfsson, Helgi I., Di Natale, Francesco, Lightstone, Felice C., and Gnanakaran, S. Capturing Phase Behavior of Ternary Lipid Mixtures with a Refined Martini Coarse-Grained Force Field. United States: N. p., 2018. Web. doi:10.1021/acs.jctc.8b00496.
Carpenter, Timothy S., López, Cesar A., Neale, Chris, Montour, Cameron, Ingólfsson, Helgi I., Di Natale, Francesco, Lightstone, Felice C., & Gnanakaran, S. Capturing Phase Behavior of Ternary Lipid Mixtures with a Refined Martini Coarse-Grained Force Field. United States. doi:10.1021/acs.jctc.8b00496.
Carpenter, Timothy S., López, Cesar A., Neale, Chris, Montour, Cameron, Ingólfsson, Helgi I., Di Natale, Francesco, Lightstone, Felice C., and Gnanakaran, S. Tue . "Capturing Phase Behavior of Ternary Lipid Mixtures with a Refined Martini Coarse-Grained Force Field". United States. doi:10.1021/acs.jctc.8b00496. https://www.osti.gov/servlets/purl/1512613.
@article{osti_1512613,
title = {Capturing Phase Behavior of Ternary Lipid Mixtures with a Refined Martini Coarse-Grained Force Field},
author = {Carpenter, Timothy S. and López, Cesar A. and Neale, Chris and Montour, Cameron and Ingólfsson, Helgi I. and Di Natale, Francesco and Lightstone, Felice C. and Gnanakaran, S.},
abstractNote = {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. We refine the CG Martini parameters for the high- and low-melting temperature (Tm) 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.},
doi = {10.1021/acs.jctc.8b00496},
journal = {Journal of Chemical Theory and Computation},
number = 11,
volume = 14,
place = {United States},
year = {2018},
month = {9}
}

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