The use of a generalized born model for the analysis of protein conformational transitions: A comparative study with explicit solvent simulations for chemotaxis Y protein (CheY)

To investigate whether implicit solvent models are appropriate for mechanistic studies of conformational transition in proteins, a recently developed generalized Born model (GBSW) was applied to a small signaling protein, chemotaxis protein Y (CheY), with different combinations of the phosphorylation state and conformation of the system; the results were compared to explicit solvent simulations using a stochastic boundary condition. The subtle but distinct conformational transitions involved in CheY activation makes the system ideally suited for comparing implicit and explicit solvent models because these conformational transitions are potentially accessible in both types of simulations. The structural and dynamical properties analyzed include not only those localized to the active site region but also throughout the protein, such as sidechain methyl group order parameters, backbone hydrogen bonding lifetime and occupancy as well as principal components of the trajectories. Overall, many properties were well reproduced by the GBSW simulations when compared with the explicit solvent calculations, although a number of observations consistently point to the suggestion that the current parameterization of the GBSW model tends to overestimate hydrogen‐bonding interactions involving both charged groups and (charge‐neutral) backbone atoms. This deficiency led to overstabilization of certain secondary structural motifs and more importantly, qualitatively different behaviors for the active site groups (Thr 87, Ala 88, the β4–α4 loop) in response to phosphorylation, when compared with explicit solvent simulations. The current study highlights the value of carrying out both explicit and implicit solvent simulations for complementary mechanistic insights in the analysis of conformational transition in biomolecules. © 2006 Wiley Periodicals, Inc. J Comput Chem, 2006

[1]  J Andrew McCammon,et al.  Limitations of atom-centered dielectric functions in implicit solvent models. , 2005, The journal of physical chemistry. B.

[2]  K. Hinsen.  Analysis of domain motions by approximate normal mode calculations , 1998, Proteins.

[3]  A. Caflisch,et al.  The role of side-chain interactions in the early steps of aggregation: Molecular dynamics simulations of an amyloid-forming peptide from the yeast prion Sup35 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[4]  K. Sanbonmatsu,et al.  α-Helical stabilization by side chain shielding of backbone hydrogen bonds , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[5]  M. Karplus,et al.  Simulation of activation free energies in molecular systems , 1996 .

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

[7]  J. Onuchic,et al.  Protein folding mediated by solvation: Water expulsion and formation of the hydrophobic core occur after the structural collapse , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  B. Berne,et al.  Can a continuum solvent model reproduce the free energy landscape of a β-hairpin folding in water? , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Andrew L. Lee,et al.  Long-range dynamic effects of point mutations propagate through side chains in the serine protease inhibitor eglin c. , 2004, Biochemistry.

[10]  D. Blair,et al.  How bacteria sense and swim. , 1995, Annual review of microbiology.

[11]  D. Wemmer,et al.  Beryllofluoride mimics phosphorylation of NtrC and other bacterial response regulators. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Bourret,et al.  Throwing the switch in bacterial chemotaxis. , 1999, Trends in microbiology.

[13]  Nathan A. Baker,et al.  Solvation forces on biomolecular structures: A comparison of explicit solvent and Poisson–Boltzmann models , 2004, J. Comput. Chem..

[14]  J. Banavar,et al.  Computer Simulation of Liquids , 1988 .

[15]  A. Roitberg,et al.  All-atom structure prediction and folding simulations of a stable protein. , 2002, Journal of the American Chemical Society.

[16]  Eric J. Sorin,et al.  Simulations of the role of water in the protein-folding mechanism. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Jianpeng Ma,et al.  A dynamic analysis of the rotation mechanism for conformational change in F(1)-ATPase. , 2002, Structure.

[18]  Ruth Nussinov,et al.  Modulating Functional Loop Movements: The Role of Highly Conserved Residues in the Correlated Loop Motions , 2004, Chembiochem : a European journal of chemical biology.

[19]  M. Karplus,et al.  The origin of protein sidechain order parameter distributions. , 2004, Journal of the American Chemical Society.

[20]  N. Go,et al.  Investigating protein dynamics in collective coordinate space. , 1999, Current opinion in structural biology.

[21]  C. Brooks,et al.  Balancing solvation and intramolecular interactions: toward a consistent generalized Born force field. , 2006, Journal of the American Chemical Society.

[22]  W. C. Still,et al.  Semianalytical treatment of solvation for molecular mechanics and dynamics , 1990 .

[23]  M. B. Pinto,et al.  Optimized δ expansion for relativistic nuclear models , 1997, nucl-th/9709049.

[24]  Matthias Buck,et al.  Internal and Overall Peptide Group Motion in Proteins: Molecular Dynamics Simulations for Lysozyme Compared with Results from X-ray and NMR Spectroscopy , 1999 .

[25]  M Karplus,et al.  Solvent effects on protein motion and protein effects on solvent motion. Dynamics of the active site region of lysozyme. , 1989, Journal of molecular biology.

[26]  C. Brooks,et al.  From folding theories to folding proteins: a review and assessment of simulation studies of protein folding and unfolding. , 2001, Annual review of physical chemistry.

[27]  D. Leitner.  Vibrational Energy Transfer in Helices , 2001 .

[28]  Seok-Yong Lee,et al.  Crystal structure of an activated response regulator bound to its target , 2001, Nature Structural Biology.

[29]  B. Honig,et al.  A hierarchical approach to all‐atom protein loop prediction , 2004, Proteins.

[30]  Sergio E. Wong,et al.  Competition between intramolecular hydrogen bonds and solvation in phosphorylated peptides: simulations with explicit and implicit solvent. , 2005, The journal of physical chemistry. B.

[31]  F M Richards,et al.  Areas, volumes, packing and protein structure. , 1977, Annual review of biophysics and bioengineering.

[32]  J. Davies,et al.  Molecular Biology of the Cell , 1983, Bristol Medico-Chirurgical Journal.

[33]  Jae Young Lee,et al.  Crystal structure and functional analysis of the SurE protein identify a novel phosphatase family , 2001, Nature Structural Biology.

[34]  Rudolph A. Marcus,et al.  Electron Transfer Reactions in Chemistry: Theory and Experiment (Nobel Lecture) , 1993 .

[35]  Viktor Hornak,et al.  Improved conformational sampling through an efficient combination of mean-field simulation approaches , 2004 .

[36]  Bernard R. Brooks,et al.  New spherical‐cutoff methods for long‐range forces in macromolecular simulation , 1994, J. Comput. Chem..

[37]  A. Sali,et al.  Evolution and physics in comparative protein structure modeling. , 2002, Accounts of chemical research.

[38]  Alexander D. MacKerell,et al.  Computational Biochemistry and Biophysics , 2001 .

[39]  Robert B. Hermann,et al.  Theory of hydrophobic bonding. II. Correlation of hydrocarbon solubility in water with solvent cavity surface area , 1972 .

[40]  D. Case,et al.  Exploring protein native states and large‐scale conformational changes with a modified generalized born model , 2004, Proteins.

[41]  C. Brooks,et al.  Novel generalized Born methods , 2002 .

[42]  Samuel H. Yalkowsky,et al.  Solubility of nonelectrolytes in polar solvents. V. Estimation of the solubility of aliphatic monofunctional compounds in water using a molecular surface area approach , 1975 .

[43]  Jianpeng Ma,et al.  A normal mode analysis of structural plasticity in the biomolecular motor F(1)-ATPase. , 2004, Journal of molecular biology.

[44]  D. Bray,et al.  Signaling complexes: biophysical constraints on intracellular communication. , 1998, Annual review of biophysics and biomolecular structure.

[45]  G. Wadhams,et al.  Making sense of it all: bacterial chemotaxis , 2004, Nature Reviews Molecular Cell Biology.

[46]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[47]  Themis Lazaridis,et al.  Thermodynamics of protein folding: a microscopic view. , 2002, Biophysical chemistry.

[48]  B. Roux,et al.  Implicit solvent models. , 1999, Biophysical chemistry.

[49]  M. Karplus,et al.  Molecular dynamics and protein function. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[50]  A. Szabó,et al.  Model-free approach to the interpretation of nuclear magnetic resonance relaxation in macromolecules. 1. Theory and range of validity , 1982 .

[51]  M. Born.  Volumen und Hydratationswärme der Ionen , 1920 .

[52]  P. Kollman,et al.  Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. , 1998, Science.

[53]  Charles L. Brooks,et al.  Application of torsion angle molecular dynamics for efficient sampling of protein conformations , 2005, J. Comput. Chem..

[54]  R. Nussinov,et al.  Is allostery an intrinsic property of all dynamic proteins? , 2004, Proteins.

[55]  Hao Hu,et al.  Increased rigidity of eglin c at acidic pH: evidence from NMR spin relaxation and MD simulations. , 2003, Biochemistry.

[56]  Peter G Wolynes,et al.  Role of water mediated interactions in protein-protein recognition landscapes. , 2003, Journal of the American Chemical Society.

[57]  A Kitao,et al.  Harmonic and anharmonic aspects in the dynamics of BPTI: A normal mode analysis and principal component analysis , 1994, Protein science : a publication of the Protein Society.

[58]  Hoover,et al.  Canonical dynamics: Equilibrium phase-space distributions. , 1985, Physical review. A, General physics.

[59]  Sergio E. Wong,et al.  Methyl Motional Parameters in Crystalline l-Alanine: Molecular Dynamics Simulation and NMR , 2000 .

[60]  J. S. Parkinson,et al.  NMR structure of activated CheY. , 2000, Journal of molecular biology.

[61]  S. Nosé.  A unified formulation of the constant temperature molecular dynamics methods , 1984 .

[62]  Sergio A Hassan,et al.  Long dynamics simulations of proteins using atomistic force fields and a continuum representation of solvent effects: Calculation of structural and dynamic properties , 2005, Proteins.

[63]  Thomas Simonson,et al.  Implicit solvent models: Combining an analytical formulation of continuum electrostatics with simple models of the hydrophobic effect , 1999 .

[64]  M. Eisenbach,et al.  Correlation between phosphorylation of the chemotaxis protein CheY and its activity at the flagellar motor. , 1992, Biochemistry.

[65]  Hervé Minoux,et al.  An electrostatic basis for the stability of thermophilic proteins , 2004, Proteins.

[66]  John M. Walker,et al.  Molecular Motors , 2007, Methods in Molecular Biology™.

[67]  T. Lazaridis,et al.  Potentials of mean force between ionizable amino acid side chains in water. , 2003, Journal of the American Chemical Society.

[68]  O Jardetzky,et al.  Protein dynamics and conformational transitions in allosteric proteins. , 1996, Progress in biophysics and molecular biology.

[69]  Fred A. Hamprecht,et al.  A strategy for analysis of (molecular) equilibrium simulations: Configuration space density estimation, clustering, and visualization , 2001 .

[70]  Barry Honig,et al.  Comparative study of generalized Born models: protein dynamics. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[71]  Aaron R Dinner,et al.  Automatic method for identifying reaction coordinates in complex systems. , 2005, The journal of physical chemistry. B.

[72]  Sergio E. Wong,et al.  Methyl dynamics in crystalline amino acids: MD and NMR , 2003, J. Comput. Chem..

[73]  Charles L. Brooks,et al.  Generalized born model with a simple smoothing function , 2003, J. Comput. Chem..

[74]  Alexander D. MacKerell,et al.  All-atom empirical potential for molecular modeling and dynamics studies of proteins. , 1998, The journal of physical chemistry. B.

[75]  Ann M Stock,et al.  Structural analysis of bacterial chemotaxis proteins: components of a dynamic signaling system. , 1998, Journal of structural biology.

[76]  Richard A. Friesner,et al.  First-Shell Solvation of Ion Pairs: Correction of Systematic Errors in Implicit Solvent Models† , 2004 .

[77]  M. Karplus,et al.  Deformable stochastic boundaries in molecular dynamics , 1983 .

[78]  M. Simon,et al.  Activation of the phosphosignaling protein CheY. I. Analysis of the phosphorylated conformation by 19F NMR and protein engineering. , 1993, The Journal of biological chemistry.

[79]  Andrew L. Lee,et al.  Relating side-chain mobility in proteins to rotameric transitions: Insights from molecular dynamics simulations and NMR , 2005, Journal of biomolecular NMR.

[80]  F. Young.  Biochemistry , 1955, The Indian Medical Gazette.

[81]  B. Honig,et al.  Classical electrostatics in biology and chemistry. , 1995, Science.

[82]  D. Beglov,et al.  Finite representation of an infinite bulk system: Solvent boundary potential for computer simulations , 1994 .

[83]  M. Karplus,et al.  Harmonic dynamics of proteins: normal modes and fluctuations in bovine pancreatic trypsin inhibitor. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[84]  B. Hess.  Convergence of sampling in protein simulations. , 2002, Physical review. E, Statistical, nonlinear, and soft matter physics.

[85]  Bojan Zagrovic,et al.  Solvent viscosity dependence of the folding rate of a small protein: Distributed computing study , 2003, J. Comput. Chem..

[86]  Hydrophobic core fluidity of homologous protein domains: relation of side-chain dynamics to core composition and packing. , 2004, Biochemistry.

[87]  A. Joshua Wand,et al.  Dynamic activation of protein function: A view emerging from NMR spectroscopy , 2001, Nature Structural Biology.

[88]  Guohui Li,et al.  A coarse-grained normal mode approach for macromolecules: an efficient implementation and application to Ca(2+)-ATPase. , 2002, Biophysical journal.

[89]  M. Karplus,et al.  Locally accessible conformations of proteins: Multiple molecular dynamics simulations of crambin , 1998, Protein science : a publication of the Protein Society.

[90]  B. Jayaram,et al.  Do water molecules mediate protein-DNA recognition? , 2001, Journal of molecular biology.

[91]  R. Zhou.  Free energy landscape of protein folding in water: Explicit vs. implicit solvent , 2003, Proteins.

[92]  Charles L. Brooks,et al.  Performance comparison of generalized born and Poisson methods in the calculation of electrostatic solvation energies for protein structures , 2004, J. Comput. Chem..

[93]  C. Brooks,et al.  Recent advances in the development and application of implicit solvent models in biomolecule simulations. , 2004, Current opinion in structural biology.

[94]  Arun Yethiraj,et al.  Solvent effects on the collapse dynamics of polymers , 2001 .

[95]  H. Nymeyer,et al.  Simulation of the folding equilibrium of α-helical peptides: A comparison of the generalized Born approximation with explicit solvent , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[96]  K. Volz,et al.  A Distinct Meta-active Conformation in the 1.1-Å Resolution Structure of Wild-type ApoCheY* , 2001, The Journal of Biological Chemistry.

[97]  S. Chervitz,et al.  The two-component signaling pathway of bacterial chemotaxis: a molecular view of signal transduction by receptors, kinases, and adaptation enzymes. , 1997, Annual review of cell and developmental biology.

[98]  Alexander D. MacKerell,et al.  An Improved Empirical Potential Energy Function for Molecular Simulations of Phospholipids , 2000 .

[99]  Mark A Olson,et al.  Modeling loop reorganization free energies of acetylcholinesterase: A comparison of explicit and implicit solvent models , 2004, Proteins.

[100]  R. Macnab,et al.  Distinct regions of bacterial flagellar switch protein FliM interact with FliG, FliN and CheY. , 1997, Journal of molecular biology.

[101]  Joan-Emma Shea,et al.  Probing the folding free energy landscape of the src-SH3 protein domain , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[102]  Q. Cui,et al.  Reconciling the “old” and “new” views of protein allostery: A molecular simulation study of chemotaxis Y protein (CheY) , 2006, Proteins.

[103]  Brian W Matthews,et al.  Structure of the constitutively active double mutant CheYD13K Y106W alone and in complex with a FliM peptide. , 2004, Journal of molecular biology.

[104]  Ad Bax,et al.  Insights into the mobility of methyl-bearing side chains in proteins from (3)J(CC) and (3)J(CN) couplings. , 2003, Journal of the American Chemical Society.

[105]  J. Mccammon,et al.  Molecular Dynamics Simulations of a Polyalanine Octapeptide under Ewald Boundary Conditions: Influence of Artificial Periodicity on Peptide Conformation , 2000 .

[106]  P. Wolynes,et al.  Water in protein structure prediction. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

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

[108]  D. Beglov,et al.  Atomic Radii for Continuum Electrostatics Calculations Based on Molecular Dynamics Free Energy Simulations , 1997 .

[109]  D. Case,et al.  Generalized born models of macromolecular solvation effects. , 2000, Annual review of physical chemistry.

[110]  Jane Clarke,et al.  What contributions to protein side-chain dynamics are probed by NMR experiments? A molecular dynamics simulation analysis. , 2005, Journal of molecular biology.

[111]  Andrew L. Lee,et al.  Redistribution and loss of side chain entropy upon formation of a calmodulin–peptide complex , 2000, Nature Structural Biology.

[112]  Christoph Dellago,et al.  Kinetic pathways of ion pair dissociation in water , 1999 .

[113]  M. Levitt,et al.  Refinement of protein conformations using a macromolecular energy minimization procedure. , 1969, Journal of molecular biology.

[114]  Bernard R. Brooks,et al.  Molecular Dynamics of Staphylococcal Nuclease: Comparison of Simulation with 15N and 13C NMR Relaxation Data , 1998 .