A comparison of coarse-grained and continuum models for membrane bending in lipid bilayer fusion pores.

To establish the validity of continuum mechanics models quantitatively for the analysis of membrane remodeling processes, we compare the shape and energies of the membrane fusion pore predicted by coarse-grained (MARTINI) and continuum mechanics models. The results at these distinct levels of resolution give surprisingly consistent descriptions for the shape of the fusion pore, and the deviation between the continuum and coarse-grained models becomes notable only when the radius of curvature approaches the thickness of a monolayer. Although slow relaxation beyond microseconds is observed in different perturbative simulations, the key structural features (e.g., dimension and shape of the fusion pore near the pore center) are consistent among independent simulations. These observations provide solid support for the use of coarse-grained and continuum models in the analysis of membrane remodeling. The combined coarse-grained and continuum analysis confirms the recent prediction of continuum models that the fusion pore is a metastable structure and that its optimal shape is neither toroidal nor catenoidal. Moreover, our results help reveal a new, to our knowledge, bowing feature in which the bilayers close to the pore axis separate more from one another than those at greater distances from the pore axis; bowing helps reduce the curvature and therefore stabilizes the fusion pore structure. The spread of the bilayer deformations over distances of hundreds of nanometers and the substantial reduction in energy of fusion pore formation provided by this spread indicate that membrane fusion can be enhanced by allowing a larger area of membrane to participate and be deformed.

[1]  Gregory A Voth,et al.  Reconstructing protein remodeled membranes in molecular detail from mesoscopic models. , 2011, Physical chemistry chemical physics : PCCP.

[2]  F S Cohen,et al.  Membrane mechanics can account for fusion pore dilation in stages. , 1995, Biophysical journal.

[3]  J. Kindt,et al.  Bilayer edge and curvature effects on partitioning of lipids by tail length: atomistic simulations. , 2008, Biophysical journal.

[4]  Kozlov Mm,et al.  On the Theory of Membrane Fusion. The Stalk Mechanism , 1984 .

[5]  Michael M. Kozlov,et al.  How proteins produce cellular membrane curvature , 2006, Nature Reviews Molecular Cell Biology.

[6]  M. Mueller,et al.  Field theoretic study of bilayer membrane fusion. I. Hemifusion mechanism. , 2003, Biophysical journal.

[7]  Harvey T. McMahon,et al.  Membrane Curvature in Synaptic Vesicle Fusion and Beyond , 2010, Cell.

[8]  Q. Cui,et al.  A New Coarse-Grained Force Field for Membrane-Peptide Simulations. , 2011, Journal of chemical theory and computation.

[9]  Yoko Shibata,et al.  Mechanisms shaping the membranes of cellular organelles. , 2009, Annual review of cell and developmental biology.

[10]  R. Epand,et al.  The mechanism of lamellar-to-inverted hexagonal phase transitions in phosphatidylethanolamine: implications for membrane fusion mechanisms. , 1997, Biophysical journal.

[11]  A. J. Markvoort,et al.  Lipid acrobatics in the membrane fusion arena. , 2011, Current topics in membranes.

[12]  D. Marsh,et al.  Elastic curvature constants of lipid monolayers and bilayers. , 2006, Chemistry and physics of lipids.

[13]  D. Tieleman,et al.  The MARTINI force field: coarse grained model for biomolecular simulations. , 2007, The journal of physical chemistry. B.

[14]  Klaus Schulten,et al.  Quasicontinuum Representations of Atomic-Scale Mechanics: From Proteins to Dislocations , 2002 .

[15]  Alexander D. MacKerell,et al.  Development of the CHARMM Force Field for Lipids. , 2011, The journal of physical chemistry letters.

[16]  George Khelashvili,et al.  Quantitative modeling of membrane deformations by multihelical membrane proteins: application to G-protein coupled receptors. , 2011, Biophysical journal.

[17]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[18]  R. Epand,et al.  Effects of Spontaneous Bilayer Curvature on Influenza Virus–mediated Fusion Pores , 1998, The Journal of general physiology.

[19]  V. Markin,et al.  Membrane fusion: stalk model revisited. , 2002, Biophysical journal.

[20]  D. Boal,et al.  Mechanics of the cell , 2001 .

[21]  M. Kozlov,et al.  Protein-lipid interplay in fusion and fission of biological membranes. , 2003, Annual review of biochemistry.

[22]  Gerrit Groenhof,et al.  GROMACS: Fast, flexible, and free , 2005, J. Comput. Chem..

[23]  F. Brown.  Continuum simulations of biomembrane dynamics and the importance of hydrodynamic effects , 2011, Quarterly Reviews of Biophysics.

[24]  Marcus Mueller,et al.  Field theoretic study of bilayer membrane fusion , 2004 .

[25]  M. Kozlov,et al.  Mechanics of membrane fusion , 2008, Nature Structural &Molecular Biology.

[26]  F. Brown.  Elastic modeling of biomembranes and lipid bilayers. , 2008, Annual review of physical chemistry.

[27]  Q. Cui,et al.  Three-dimensional stress field around a membrane protein: atomistic and coarse-grained simulation analysis of gramicidin A. , 2013, Biophysical journal.

[28]  M. Jackson.  Inferring structures of kinetic intermediates in Ca(2+)-triggered exocytosis. , 2011, Current topics in membranes.

[29]  M. Kozlov,et al.  Stalk mechanism of vesicle fusion , 1989, European Biophysics Journal.

[30]  M. Jackson.  Minimum Membrane Bending Energies of Fusion Pores , 2009, Journal of Membrane Biology.

[31]  V. Pande,et al.  Water ordering at membrane interfaces controls fusion dynamics. , 2011, Journal of the American Chemical Society.

[32]  D. Siegel.  The modified stalk mechanism of lamellar/inverted phase transitions and its implications for membrane fusion. , 1999, Biophysical journal.

[33]  Helmut Grubmüller,et al.  How SNARE molecules mediate membrane fusion: recent insights from molecular simulations. , 2012, Current opinion in structural biology.

[34]  J. Zimmerberg,et al.  Flickering fusion pores comparable with initial exocytotic pores occur in protein-free phospholipid bilayers. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Lindau,et al.  The fusion pore. , 2003, Biochimica et biophysica acta.

[36]  W. Gelbart,et al.  Molecular theory of curvature elasticity in surfactant films , 1990 .

[37]  M. Jackson,et al.  The fusion pores of Ca2+-triggered exocytosis , 2008, Nature Structural &Molecular Biology.

[38]  G. Voth,et al.  Multiscale simulation of protein mediated membrane remodeling. , 2010, Seminars in cell & developmental biology.

[39]  Q. Cui,et al.  Membrane-mediated protein-protein interactions and connection to elastic models: a coarse-grained simulation analysis of gramicidin A association. , 2013, Biophysical journal.

[40]  Q. Cui,et al.  Curvature generation and pressure profile modulation in membrane by lysolipids: insights from coarse-grained simulations. , 2009, Biophysical journal.

[41]  George Khelashvili,et al.  Protein Diffusion on Charged Membranes: A Dynamic Mean-Field Model Describes Time Evolution and Lipid Reorganization , 2007, Biophysical journal.

[42]  Peter M. Kasson,et al.  Ensemble molecular dynamics yields submillisecond kinetics and intermediates of membrane fusion , 2006, Proceedings of the National Academy of Sciences.

[43]  W. Helfrich.  Elastic Properties of Lipid Bilayers: Theory and Possible Experiments , 1973, Zeitschrift fur Naturforschung. Teil C: Biochemie, Biophysik, Biologie, Virologie.

[44]  Yonathan Kozlovsky,et al.  Stalk model of membrane fusion: solution of energy crisis. , 2002, Biophysical journal.

[45]  Gregory A Voth,et al.  Multiscale modeling of biomolecular systems: in serial and in parallel. , 2007, Current opinion in structural biology.

[46]  Peter M. Kasson,et al.  Atomic-Resolution Simulations Predict a Transition State for Vesicle Fusion Defined by Contact of a Few Lipid Tails , 2010, PLoS Comput. Biol..

[47]  Lin Yang,et al.  Observation of a Membrane Fusion Intermediate Structure , 2002, Science.

[48]  Y. Bouret,et al.  Molecular dynamics simulations of the lipid bilayer edge. , 2004, Biophysical journal.

[49]  K. Schulten,et al.  Structural dynamics of the lac repressor-DNA complex revealed by a multiscale simulation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[50]  M. Kozlov,et al.  The gaussian curvature elastic modulus of N-monomethylated dioleoylphosphatidylethanolamine: relevance to membrane fusion and lipid phase behavior. , 2004, Biophysical journal.