Coarse Grained Molecular Dynamics Simulations of Transmembrane Protein-Lipid Systems

Many biological cellular processes occur at the micro- or millisecond time scale. With traditional all-atom molecular modeling techniques it is difficult to investigate the dynamics of long time scales or large systems, such as protein aggregation or activation. Coarse graining (CG) can be used to reduce the number of degrees of freedom in such a system, and reduce the computational complexity. In this paper the first version of a coarse grained model for transmembrane proteins is presented. This model differs from other coarse grained protein models due to the introduction of a novel angle potential as well as a hydrogen bonding potential. These new potentials are used to stabilize the backbone. The model has been validated by investigating the adaptation of the hydrophobic mismatch induced by the insertion of WALP-peptides into a lipid membrane, showing that the first step in the adaptation is an increase in the membrane thickness, followed by a tilting of the peptide.

[1]  R. Koeppe,et al.  Orientation and motion of tryptophan interfacial anchors in membrane-spanning peptides. , 2007, Biochemistry.

[2]  Klaus Schulten,et al.  Coarse grained protein-lipid model with application to lipoprotein particles. , 2006, The journal of physical chemistry. B.

[3]  Peter L. Freddolino,et al.  The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[4]  V. Cherezov,et al.  Transmembrane peptides stabilize inverted cubic phases in a biphasic length-dependent manner: implications for protein-induced membrane fusion. , 2006, Biophysical journal.

[5]  S. Bhattacharjee,et al.  Molecular dynamics simulation study of interaction between a class IIa bacteriocin and its immunity protein. , 2007, Biochimica et biophysica acta.

[6]  M. Klein,et al.  Simulation of Diblock Copolymer Self-Assembly, Using a Coarse-Grain Model , 2004 .

[7]  Yundong Wu,et al.  Coarse-Grained Protein Model Coupled with a Coarse-Grained Water Model:  Molecular Dynamics Study of Polyalanine-Based Peptides. , 2007, Journal of chemical theory and computation.

[8]  J. Killian,et al.  Sensitivity of single membrane-spanning alpha-helical peptides to hydrophobic mismatch with a lipid bilayer: effects on backbone structure, orientation, and extent of membrane incorporation. , 2001, Biochemistry.

[9]  J. Killian,et al.  Lipid dependence of membrane anchoring properties and snorkeling behavior of aromatic and charged residues in transmembrane peptides. , 2002, Biochemistry.

[10]  Paj Peter Hilbers,et al.  Vesicle shapes from molecular dynamics simulations. , 2006, The journal of physical chemistry. B.

[11]  B. Kobilka.  G protein coupled receptor structure and activation. , 2007, Biochimica et biophysica acta.

[12]  Erik Strandberg,et al.  Tilt angles of transmembrane model peptides in oriented and non-oriented lipid bilayers as determined by 2H solid-state NMR. , 2004, Biophysical journal.

[13]  H. C. Andersen,et al.  Role of Repulsive Forces in Determining the Equilibrium Structure of Simple Liquids , 1971 .

[14]  Michael L. Klein,et al.  A coarse grain model for n-alkanes parameterized from surface tension data , 2003 .

[15]  M. Ulmschneider,et al.  Folding Peptides into Lipid Bilayer Membranes. , 2008, Journal of chemical theory and computation.

[16]  R. Zare,et al.  Single-molecule spectroscopy of the β2 adrenergic receptor: Observation of conformational substates in a membrane protein , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Thomas Huber,et al.  G protein-coupled receptors self-assemble in dynamics simulations of model bilayers. , 2007, Journal of the American Chemical Society.

[18]  Jeremy C. Smith,et al.  Understanding the energetics of helical peptide orientation in membranes , 2005, Proteins.

[19]  C. Brooks,et al.  Interfacial folding and membrane insertion of designed peptides studied by molecular dynamics simulations. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Larson,et al.  Structure, topology, and tilt of cell-signaling peptides containing nuclear localization sequences in membrane bilayers determined by solid-state NMR and molecular dynamics simulation studies. , 2007, Biochemistry.

[21]  Klaus Schulten,et al.  Stability and dynamics of virus capsids described by coarse-grained modeling. , 2006, Structure.

[22]  P. Derreumaux,et al.  A coarse‐grained protein force field for folding and structure prediction , 2007, Proteins.

[23]  M. Levitt.  A simplified representation of protein conformations for rapid simulation of protein folding. , 1976, Journal of molecular biology.

[24]  Martin B Ulmschneider,et al.  Properties of integral membrane protein structures: Derivation of an implicit membrane potential , 2005, Proteins.

[25]  A. Wallqvist,et al.  A simplified amino acid potential for use in structure predictions of proteins , 1994, Proteins.

[26]  Roland Faller.  Automatic coarse graining of polymers , 2004 .

[27]  J. Killian,et al.  Influence of lipid/peptide hydrophobic mismatch on the thickness of diacylphosphatidylcholine bilayers. A 2H NMR and ESR study using designed transmembrane alpha-helical peptides and gramicidin A. , 1998, Biochemistry.

[28]  J. Killian,et al.  Hydrophobic matching mechanism investigated by molecular dynamics simulations , 2002 .

[29]  Gregory A Voth,et al.  Coarse-grained peptide modeling using a systematic multiscale approach. , 2007, Biophysical journal.

[30]  J. Killian,et al.  The effect of peptide/lipid hydrophobic mismatch on the phase behavior of model membranes mimicking the lipid composition in Escherichia coli membranes. , 2000, Biophysical journal.

[31]  Xuejin Li,et al.  Developing a coarse-grained force field for the diblock copolymer poly(styrene-b-butadiene) from atomistic simulation. , 2006, The Journal of chemical physics.

[32]  R. Larson,et al.  The MARTINI Coarse-Grained Force Field: Extension to Proteins. , 2008, Journal of chemical theory and computation.

[33]  James B. Adams,et al.  Interatomic Potentials from First-Principles Calculations: The Force-Matching Method , 1993, cond-mat/9306054.

[34]  M. Klein,et al.  Computer simulation studies of biomembranes using a coarse grain model , 2002 .

[35]  Timothy S. Carpenter,et al.  Self-assembly of a simple membrane protein: coarse-grained molecular dynamics simulations of the influenza M2 channel. , 2008, Biophysical journal.

[36]  Gregory A Voth,et al.  A multiscale coarse-graining method for biomolecular systems. , 2005, The journal of physical chemistry. B.

[37]  Klaus Schulten,et al.  Molecular dynamics investigation of primary photoinduced events in the activation of rhodopsin. , 2002, Biophysical journal.

[38]  B. Kobilka.  Agonist-induced conformational changes in the beta2 adrenergic receptor. , 2002, The journal of peptide research : official journal of the American Peptide Society.

[39]  A. J. Markvoort,et al.  The bilayer-vesicle transition is entropy driven. , 2005, The journal of physical chemistry. B.

[40]  Peter L. Freddolino,et al.  Prediction of structure and function of G protein-coupled receptors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Salgado,et al.  The dynamic orientation of membrane-bound peptides: bridging simulations and experiments. , 2007, Biophysical journal.

[42]  Adam Liwo,et al.  Optimization of the UNRES Force Field by Hierarchical Design of the Potential-Energy Landscape. 1. Tests of the Approach Using Simple Lattice Protein Models , 2004 .

[43]  J. Killian,et al.  On the orientation of a designed transmembrane peptide: toward the right tilt angle? , 2007, Journal of the American Chemical Society.

[44]  R. C. Reeder,et al.  A Coarse Grain Model for Phospholipid Simulations , 2001 .

[45]  V. Lemaître,et al.  Solid-state 17O NMR as a probe for structural studies of proteins in biomembranes. , 2004, Journal of the American Chemical Society.

[46]  M. Sansom,et al.  Coarse-grained molecular dynamics simulations of the energetics of helix insertion into a lipid bilayer. , 2008, Biochemistry.

[47]  J. Valverde.  Molecular Modelling: Principles and Applications , 2001 .

[48]  Gregory A Voth,et al.  Multiscale coarse graining of liquid-state systems. , 2005, The Journal of chemical physics.

[49]  Syma Khalid,et al.  Coarse-grained molecular dynamics simulations of membrane proteins and peptides. , 2007, Journal of structural biology.

[50]  K. Esselink,et al.  Computer simulations of a water/oil interface in the presence of micelles , 1990, Nature.

[51]  Adam Liwo,et al.  A united-residue force field for off-lattice protein-structure simulations. II. Parameterization of short-range interactions and determination of weights of energy terms by Z-score optimization , 1997, J. Comput. Chem..

[52]  Paj Peter Hilbers,et al.  Vesicle deformation by draining: geometrical and topological shape changes. , 2009, The journal of physical chemistry. B.

[53]  Dirk Reith,et al.  Deriving effective mesoscale potentials from atomistic simulations , 2002, J. Comput. Chem..

[54]  H. Nymeyer,et al.  Folding is not required for bilayer insertion: Replica exchange simulations of an α‐helical peptide with an explicit lipid bilayer , 2004, Proteins.

[55]  Paj Peter Hilbers,et al.  Lipid-based mechanisms for vesicle fission. , 2007, The journal of physical chemistry. B.

[56]  A. A. Louis,et al.  Accurate effective pair potentials for polymer solutions , 2000 .

[57]  W F Drew Bennett,et al.  Distribution of amino acids in a lipid bilayer from computer simulations. , 2008, Biophysical journal.

[58]  Jiyoung Heo,et al.  Prediction of the 3D Structure of FMRF‐amide Neuropeptides Bound to the Mouse MrgC11 GPCR and Experimental Validation , 2007, Chembiochem : a European journal of chemical biology.

[59]  Adam Liwo,et al.  A united-residue force field for off-lattice protein-structure simulations. I. Functional forms and parameters of long-range side-chain interaction potentials from protein crystal data , 1997, J. Comput. Chem..

[60]  H. Lodish.  Molecular Cell Biology , 1986 .

[61]  Abdelazize Laoui,et al.  Prediction of the 3D structure and dynamics of human DP G-protein coupled receptor bound to an agonist and an antagonist. , 2007, Journal of the American Chemical Society.

[62]  Florian Müller-Plathe,et al.  Coarse-graining in polymer simulation: from the atomistic to the mesoscopic scale and back. , 2002, Chemphyschem : a European journal of chemical physics and physical chemistry.

[63]  A. J. Markvoort,et al.  A detailed look at vesicle fusion. , 2006, The journal of physical chemistry. B.

[64]  Adam Liwo,et al.  Optimization of the UNRES Force Field by Hierarchical Design of the Potential-Energy Landscape. 2. Off-Lattice Tests of the Method with Single Proteins , 2004 .

[65]  Peter J Bond,et al.  Bilayer deformation by the Kv channel voltage sensor domain revealed by self-assembly simulations , 2007, Proceedings of the National Academy of Sciences.

[66]  C. Chothia.  Structural invariants in protein folding , 1975, Nature.

[67]  J. Killian,et al.  Visualization of highly ordered striated domains induced by transmembrane peptides in supported phosphatidylcholine bilayers. , 2000, Biochemistry.

[68]  Peter J Bond,et al.  Insertion and assembly of membrane proteins via simulation. , 2006, Journal of the American Chemical Society.

[69]  M. Cieplak,et al.  Coarse grained description of protein folding , 1998, cond-mat/9806178.

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

[71]  R. Larson,et al.  Molecular dynamics simulations of model trans-membrane peptides in lipid bilayers: a systematic investigation of hydrophobic mismatch. , 2006, Biophysical journal.

[72]  A. Mark,et al.  Coarse grained model for semiquantitative lipid simulations , 2004 .

[73]  Peter L. Freddolino,et al.  Predicted 3D structure for the human beta 2 adrenergic receptor and its binding site for agonists and antagonists. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[74]  Xuejin Li,et al.  Developing coarse-grained force fields for cis-poly(1,4-butadiene) from the atomistic simulation , 2005 .

[75]  W. Klug,et al.  Mechanical modeling of viral capsids , 2007 .

[76]  M. Sperotto,et al.  Characterization of the thermotropic behavior and lateral organization of lipid-peptide mixtures by a combined experimental and theoretical approach: effects of hydrophobic mismatch and role of flanking residues. , 2002, Biophysical journal.

[77]  Gregory A. Voth,et al.  The multiscale challenge for biomolecular systems: coarse-grained modeling , 2006 .

[78]  Peter L. Freddolino,et al.  Dynamic behavior of fully solvated beta2-adrenergic receptor, embedded in the membrane with bound agonist or antagonist. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[79]  J. W. Humberston.  Classical mechanics , 1980, Nature.

[80]  J. Killian,et al.  Synthetic peptides as models for intrinsic membrane proteins , 2003, FEBS letters.

[81]  A F Smeijers,et al.  Coarse-grained transmembrane proteins: hydrophobic matching, aggregation, and their effect on fusion. , 2006, The journal of physical chemistry. B.

[82]  C. Poole,et al.  Classical Mechanics, 3rd ed. , 2002 .

[83]  J. Salgado,et al.  Self-assembling of peptide/membrane complexes by atomistic molecular dynamics simulations. , 2007, Biophysical journal.