CafeMol: A Coarse-Grained Biomolecular Simulator for Simulating Proteins at Work.

For simulating proteins at work in millisecond time scale or longer, we develop a coarse-grained (CG) molecular dynamics (MD) method and software, CafeMol. At the resolution of one-particle-per-residue, CafeMol equips four structure-based protein models: (1) the off-lattice Go model, (2) the atomic interaction based CG model for native state and folding dynamics, (3) the multiple-basin model for conformational change dynamics, and (4) the elastic network model for quasiharmonic fluctuations around the native structure. Ligands can be treated either explicitly or implicitly. For mimicking functional motions of proteins driven by some external force, CafeMol has various and flexible means to "switch" the energy functions that induce active motions of the proteins. CafeMol can do parallel computation with modest sized PC clusters. We describe CafeMol methods and illustrate it with several examples, such as rotary motions of F1-ATPase and drug exports from a transporter. The CafeMol source code is available at www.cafemol.org .

[1]  Tirion,et al.  Large Amplitude Elastic Motions in Proteins from a Single-Parameter, Atomic Analysis. , 1996, Physical review letters.

[2]  D. Thirumalai,et al.  Kinetics of protein folding: Nucleation mechanism, time scales, and pathways , 1995 .

[3]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

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

[5]  Jeremy C. Smith,et al.  REACH: A program for coarse-grained biomolecular simulation , 2009, Comput. Phys. Commun..

[6]  J. Onuchic,et al.  Topological and energetic factors: what determines the structural details of the transition state ensemble and "en-route" intermediates for protein folding? An investigation for small globular proteins. , 2000, Journal of molecular biology.

[7]  Satoshi Murakami,et al.  Crystal structures of a multidrug transporter reveal a functionally rotating mechanism , 2006, Nature.

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

[9]  P. Boyer,et al.  The binding change mechanism for ATP synthase--some probabilities and possibilities. , 1993, Biochimica et biophysica acta.

[10]  J. Onuchic,et al.  Multiple-basin energy landscapes for large-amplitude conformational motions of proteins: Structure-based molecular dynamics simulations , 2006, Proceedings of the National Academy of Sciences.

[11]  Y. Sugita,et al.  Multidimensional replica-exchange method for free-energy calculations , 2000, cond-mat/0009120.

[12]  V. Hornak,et al.  Comparison of multiple Amber force fields and development of improved protein backbone parameters , 2006, Proteins.

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

[14]  S. Takada,et al.  Frustration, specific sequence dependence, and nonlinearity in large-amplitude fluctuations of allosteric proteins , 2011, Proceedings of the National Academy of Sciences.

[15]  J. Onuchic,et al.  Protein folding funnels: a kinetic approach to the sequence-structure relationship. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Shoji Takada,et al.  How protein thermodynamics and folding mechanisms are altered by the chaperonin cage: Molecular simulations , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Hassan A. Karimi,et al.  oGNM: online computation of structural dynamics using the Gaussian Network Model , 2006, Nucleic Acids Res..

[18]  S. Takada,et al.  Roles of native topology and chain-length scaling in protein folding: a simulation study with a Go-like model. , 2001, Journal of molecular biology.

[19]  Gerhard Hummer,et al.  Slow protein conformational dynamics from multiple experimental structures: the helix/sheet transition of arc repressor. , 2005, Structure.

[20]  S. Takada.  Go-ing for the prediction of protein folding mechanisms. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Changbong Hyeon,et al.  Dynamics of allosteric transitions in GroEL , 2006, Proceedings of the National Academy of Sciences.

[22]  D. Case,et al.  Modification of the Generalized Born Model Suitable for Macromolecules , 2000 .

[23]  David Baker,et al.  Experiment and theory highlight role of native state topology in SH3 folding , 1999, Nature Structural Biology.

[24]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[25]  Shoji Takada,et al.  Folding-based molecular simulations reveal mechanisms of the rotary motor F1-ATPase. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[26]  N. Go,et al.  Studies on protein folding, unfolding and fluctuations by computer simulation. I. The effect of specific amino acid sequence represented by specific inter-unit interactions. , 2009 .

[27]  John Karanicolas,et al.  The origins of asymmetry in the folding transition states of protein L and protein G , 2002, Protein science : a publication of the Protein Society.

[28]  Kazuhiro Oiwa,et al.  Cooperative three-step motions in catalytic subunits of F1-ATPase correlate with 80° and 40° substep rotations , 2008, Nature Structural &Molecular Biology.

[29]  Shoji Takada,et al.  Paddling mechanism for the substrate translocation by AAA+ motor revealed by multiscale molecular simulations , 2009, Proceedings of the National Academy of Sciences.

[30]  J. Onuchic,et al.  Funnels, pathways, and the energy landscape of protein folding: A synthesis , 1994, Proteins.

[31]  Shoji Takada,et al.  Optimizing physical energy functions for protein folding , 2003, Proteins.

[32]  Y. Sugita,et al.  Replica-exchange molecular dynamics method for protein folding , 1999 .

[33]  Steve Plimpton,et al.  Fast parallel algorithms for short-range molecular dynamics , 1993 .

[34]  W. Kabsch,et al.  Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features , 1983, Biopolymers.

[35]  Changbong Hyeon,et al.  Internal strain regulates the nucleotide binding site of the kinesin leading head , 2007, Proceedings of the National Academy of Sciences.

[36]  Cecilia Clementi,et al.  Coarse-grained models of protein folding: toy models or predictive tools? , 2008, Current opinion in structural biology.

[37]  Robert K Z Tan,et al.  YUP: A Molecular Simulation Program for Coarse-Grained and Multi-Scaled Models. , 2006, Journal of chemical theory and computation.

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

[39]  P. Wolynes,et al.  Spin glasses and the statistical mechanics of protein folding. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Jan Pieter Abrahams,et al.  Structure at 2.8 Â resolution of F1-ATPase from bovine heart mitochondria , 1994, Nature.

[41]  Hiroyuki Noji,et al.  Correlation between the conformational states of F1-ATPase as determined from its crystal structure and single-molecule rotation , 2008, Proceedings of the National Academy of Sciences.

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

[43]  N. Go.  Theoretical studies of protein folding. , 1983, Annual review of biophysics and bioengineering.

[44]  Shoji Takada,et al.  SimFold energy function for de novo protein structure prediction: Consensus with Rosetta , 2005, Proteins.

[45]  H. Noguchi,et al.  Self-assembly of amphiphiles into vesicles: a Brownian dynamics simulation. , 2001, Physical review. E, Statistical, nonlinear, and soft matter physics.

[46]  S. Takada,et al.  On the Hamiltonian replica exchange method for efficient sampling of biomolecular systems: Application to protein structure prediction , 2002 .

[47]  Hiroyasu Itoh,et al.  Coupling of Rotation and Catalysis in F1-ATPase Revealed by Single-Molecule Imaging and Manipulation , 2007, Cell.

[48]  I. Bahar,et al.  Gaussian Dynamics of Folded Proteins , 1997 .

[49]  D Thirumalai,et al.  The nature of folded states of globular proteins , 1992, Biopolymers.

[50]  Matthias Troyer,et al.  Feedback-optimized parallel tempering Monte Carlo , 2006, cond-mat/0602085.

[51]  Laxmikant V. Kalé,et al.  Scalable molecular dynamics with NAMD , 2005, J. Comput. Chem..

[52]  Qiang Lu,et al.  Single molecule conformational dynamics of adenylate kinase: energy landscape, structural correlations, and transition state ensembles. , 2008, Journal of the American Chemical Society.

[53]  S. Takada,et al.  Dynamic energy landscape view of coupled binding and protein conformational change: Induced-fit versus population-shift mechanisms , 2008, Proceedings of the National Academy of Sciences.

[54]  Jeffrey K. Noel,et al.  SMOG@ctbp: simplified deployment of structure-based models in GROMACS , 2010, Nucleic Acids Res..

[55]  Berk Hess,et al.  GROMACS 3.0: a package for molecular simulation and trajectory analysis , 2001 .

[56]  M. Magnasco,et al.  Forced thermal ratchets. , 1993, Physical review letters.

[57]  Kazuhiko Kinosita,et al.  Direct observation of the rotation of F1-ATPase , 1997, Nature.

[58]  Peter A. Kollman,et al.  AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules , 1995 .

[59]  Michael L. Klein,et al.  Simulations of Phospholipids Using a Coarse Grain Model , 2001 .

[60]  Valentina Tozzini,et al.  Coarse-grained models for proteins. , 2005, Current opinion in structural biology.

[61]  Shoji Takada,et al.  Drug export and allosteric coupling in a multidrug transporter revealed by molecular simulations , 2010, Nature communications.

[62]  Joanna Trylska,et al.  RedMD—Reduced molecular dynamics package , 2009, J. Comput. Chem..

[63]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[64]  M. Levitt,et al.  Computer simulation of protein folding , 1975, Nature.