Monte Carlo simulations of peptide–membrane interactions with the MCPep web server†

The MCPep server (http://bental.tau.ac.il/MCPep/) is designed for non-experts wishing to perform Monte Carlo (MC) simulations of helical peptides in association with lipid membranes. MCPep is a web implementation of a previously developed MC simulation model. The model has been tested on a variety of peptides and protein fragments. The simulations successfully reproduced available empirical data and provided new molecular insights, such as the preferred locations of peptides in the membrane and the contribution of individual amino acids to membrane association. MCPep simulates the peptide in the aqueous phase and membrane environments, both described implicitly. In the former, the peptide is subjected solely to internal conformational changes, and in the latter, each MC cycle includes additional external rigid body rotational and translational motions to allow the peptide to change its location in the membrane. The server can explore the interaction of helical peptides of any amino-acid composition with membranes of various lipid compositions. Given the peptide’s sequence or structure and the natural width and surface charge of the membrane, MCPep reports the main determinants of peptide–membrane interactions, e.g. average location and orientation in the membrane, free energy of membrane association and the peptide’s helical content. Snapshots of example simulations are also provided.

[1]  D. Marsh,et al.  Energetics of hydrophobic matching in lipid-protein interactions. , 2008, Biophysical journal.

[2]  Raz Jelinek,et al.  Membrane interactions of novicidin, a novel antimicrobial peptide: phosphatidylglycerol promotes bilayer insertion. , 2010, The journal of physical chemistry. B.

[3]  E. Martz.  Introduction to proteins—structure, function, and motion , 2012 .

[4]  N. Ben-Tal,et al.  Implicit solvent model studies of the interactions of the influenza hemagglutinin fusion peptide with lipid bilayers. , 2001, Biophysical journal.

[5]  Helmut Grubmüller,et al.  Molecular Anatomy of a Trafficking Organelle , 2006, Cell.

[6]  Nir Ben-Tal,et al.  Free energy determinants of peptide association with lipid bilayers , 2002 .

[7]  J. Rothman,et al.  Energetics and dynamics of SNAREpin folding across lipid bilayers , 2007, Nature Structural &Molecular Biology.

[8]  Nir Ben-Tal,et al.  Membrane integration of a mitochondrial signal-anchored protein does not require additional proteinaceous factors. , 2012, The Biochemical journal.

[9]  Nir Ben-Tal,et al.  Monte Carlo studies of folding, dynamics, and stability in alpha-helices. , 2005, Biophysical journal.

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

[11]  Barry Honig,et al.  Calculation of Alkane to Water Solvation Free Energies Using Continuum Solvent Models , 1996 .

[12]  R. Balaban,et al.  Skeletal muscle NAD(P)H two-photon fluorescence microscopy in vivo: topology and optical inner filters. , 2005, Biophysical journal.

[13]  A. Ben-Shaul,et al.  A molecular model for lipid-protein interaction in membranes: the role of hydrophobic mismatch. , 1993, Biophysical journal.

[14]  D. Marsh,et al.  Binding of peripheral proteins to mixed lipid membranes: effect of lipid demixing upon binding. , 1999, Biophysical journal.

[15]  Nir Ben-Tal,et al.  Stability of an ion channel in lipid bilayers: implicit solvent model calculations with gramicidin. , 2002, Biochemistry.

[16]  Dirk Fasshauer,et al.  Is Assembly of the SNARE Complex Enough to Fuel Membrane Fusion? , 2009, Journal of Biological Chemistry.

[17]  N. Metropolis,et al.  Equation of State Calculations by Fast Computing Machines , 1953, Resonance.

[18]  B Honig,et al.  Free-energy determinants of alpha-helix insertion into lipid bilayers. , 1996, Biophysical journal.

[19]  K. Schulten,et al.  Computational studies of membrane channels. , 2004, Structure.

[20]  Vladimir Parpura,et al.  Molecular form follows function: (un)snaring the SNAREs , 2008, Trends in Neurosciences.

[21]  R L Jernigan,et al.  Short‐range conformational energies, secondary structure propensities, and recognition of correct sequence‐structure matches , 1997, Proteins.

[22]  N. Ben-Tal,et al.  Interactions of hydrophobic peptides with lipid bilayers: Monte Carlo simulations with M2delta. , 2003, Biophysical journal.

[23]  George Karypis,et al.  Introduction to Protein Structure Prediction , 2010 .

[24]  Nir Ben-Tal,et al.  A combined pulse EPR and Monte Carlo simulation study provides molecular insight on peptide-membrane interactions. , 2009, The journal of physical chemistry. B.

[25]  Nir Ben-Tal,et al.  Interactions of cationic-hydrophobic peptides with lipid bilayers: a Monte Carlo simulation method. , 2007, Biophysical journal.

[26]  N. Ben-Tal,et al.  Continuum solvent model calculations of alamethicin-membrane interactions: thermodynamic aspects. , 2000, Biophysical journal.

[27]  B. Honig,et al.  Protein structure prediction: inroads to biology. , 2005, Molecular cell.

[28]  Roland L. Dunbrack,et al.  proteins STRUCTURE O FUNCTION O BIOINFORMATICS Improved prediction of protein side-chain conformations with SCWRL4 , 2022 .

[29]  Reinhard Jahn,et al.  SNAREs — engines for membrane fusion , 2006, Nature Reviews Molecular Cell Biology.

[30]  K Schulten,et al.  Calculations suggest a pathway for the transverse diffusion of a hydrophobic peptide across a lipid bilayer. , 2000, Biophysical journal.

[31]  J. Killian,et al.  Protein–lipid interactions studied with designed transmembrane peptides: role of hydrophobic matching and interfacial anchoring (Review) , 2003, Molecular membrane biology.

[32]  Nir Ben-Tal,et al.  Increased concentration of polyvalent phospholipids in the adsorption domain of a charged protein. , 2003, Biophysical journal.

[33]  S. Singer,et al.  The fluid mosaic model of the structure of cell membranes. , 1972, Science.

[34]  E. Lindahl,et al.  Membrane proteins: molecular dynamics simulations. , 2008, Current opinion in structural biology.

[35]  Syma Khalid,et al.  Antimicrobial and cell-penetrating peptides: structure, assembly and mechanisms of membrane lysis via atomistic and coarse-grained molecular dynamics simulations. , 2010, Protein and peptide letters.

[36]  D. Harries,et al.  Lipid demixing and protein-protein interactions in the adsorption of charged proteins on mixed membranes. , 2000, Biophysical journal.

[37]  Sebastian Linser,et al.  Interaction of an antimicrobial peptide with membranes: experiments and simulations with NKCS. , 2010, The journal of physical chemistry. B.

[38]  N. Ben-Tal,et al.  Monte Carlo Studies of Folding, Dynamics, and Stability in α-Helices , 2005 .