Dehydration-driven solvent exposure of hydrophobic surfaces as a driving force in peptide folding

Recent work has shown that the nature of hydration of pure hydrophobic surfaces changes with the length scale considered: water hydrogen-bonding networks adapt to small exposed hydrophobic species, hydrating or “wetting” them at relatively high densities, whereas larger hydrophobic areas are “dewetted” [Chandler D (2005), Nature 29:640–647]. Here we determine whether this effect is also present in peptides by examining the folding of a β-hairpin (the 14-residue amyloidogenic prion protein H1 peptide), using microsecond time-scale molecular dynamics simulations. Two simulation models are compared, one explicitly including the water molecules, which may thus adapt locally to peptide configurations, and the other using a popular continuum approximation, the generalized Born/surface area implicit solvent model. The results obtained show that, in explicit solvent, peptide conformers with high solvent-accessible hydrophobic surface area indeed also have low hydration density around hydrophobic residues, whereas a concomitant higher hydration density around hydrophilic residues is observed. This dewetting effect stabilizes the fully folded β-hairpin state found experimentally. In contrast, the implicit solvent model destabilizes the fully folded hairpin, tending to cluster hydrophobic residues regardless of the size of the exposed hydrophobic surface. Furthermore, the rate of the conformational transitions in the implicit solvent simulation is almost doubled with respect to that of the explicit solvent. The results suggest that dehydration-driven solvent exposure of hydrophobic surfaces may be a significant factor determining peptide conformational equilibria.

[1]  Jakob P Ulmschneider,et al.  Monte Carlo vs molecular dynamics for all-atom polypeptide folding simulations. , 2006, The journal of physical chemistry. B.

[2]  Gerhard Hummer,et al.  New perspectives on hydrophobic effects , 2000 .

[3]  Thomas M Truskett,et al.  Hydrophobic hydration from small to large lengthscales: Understanding and manipulating the crossover. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Soper,et al.  Hydration of methanol in aqueous solution. , 1993, Physical review letters.

[5]  G. Hummer,et al.  Conformational diffusion and helix formation kinetics. , 2000, Physical review letters.

[6]  A. Amadei,et al.  Thermodynamic and kinetic characterization of a β‐hairpin peptide in solution: An extended phase space sampling by molecular dynamics simulations in explicit water , 2005, Proteins.

[7]  Guido Tiana,et al.  β‐Hairpin conformation of fibrillogenic peptides: Structure and α‐β transition mechanism revealed by molecular dynamics simulations , 2004 .

[8]  A. Mark,et al.  Solvent structure at a hydrophobic protein surface , 1997, Proteins.

[9]  A. Pertsemlidis,et al.  Differences in hydration structure near hydrophobic and hydrophilic amino acids. , 1997, Biophysical journal.

[10]  Berk Hess,et al.  LINCS: A linear constraint solver for molecular simulations , 1997 .

[11]  V. Muñoz,et al.  Folding and Aggregation Kinetics of a β-Hairpin† , 2006 .

[12]  F. Gai,et al.  Nanosecond Folding Dynamics of a Three-Stranded β-Sheet , 2006 .

[13]  Pieter Rein ten Wolde,et al.  Drying-induced hydrophobic polymer collapse , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  C. Brooks,et al.  Comparative Study of the Folding Free Energy Landscape of a Three-Stranded β-Sheet Protein with Explicit and Implicit Solvent Models , 2000 .

[15]  A. Luzar.  Resolving the hydrogen bond dynamics conundrum , 2000 .

[16]  William Swope,et al.  Understanding folding and design: Replica-exchange simulations of ``Trp-cage'' miniproteins , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Peter J. Rossky,et al.  Surface topography dependence of biomolecular hydrophobic hydration , 1998, Nature.

[18]  A. Amadei,et al.  Theoretical characterization of alpha-helix and beta-hairpin folding kinetics. , 2005, Journal of the American Chemical Society.

[19]  R Nussinov,et al.  Explicit and implicit water simulations of a β‐hairpin peptide , 1999, Proteins.

[20]  J. Hofrichter,et al.  The protein folding 'speed limit'. , 2004, Current opinion in structural biology.

[21]  C. Tanford,et al.  The hydrophobic effect and the organization of living matter. , 1978, Science.

[22]  K. Dill.  Dominant forces in protein folding. , 1990, Biochemistry.

[23]  D Chandler,et al.  Temperature and length scale dependence of hydrophobic effects and their possible implications for protein folding. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[24]  W. Kauzmann.  Some factors in the interpretation of protein denaturation. , 1959, Advances in protein chemistry.

[25]  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.

[26]  B. Berne,et al.  Dewetting-induced collapse of hydrophobic particles , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[27]  D. Chandler,et al.  Hydrophobicity at Small and Large Length Scales , 1999 .

[28]  W. L. Jorgensen,et al.  Polypeptide folding using Monte Carlo sampling, concerted rotation, and continuum solvation. , 2004, Journal of the American Chemical Society.

[29]  Greg L. Hura,et al.  Determining the role of hydration forces in protein folding , 1999 .

[30]  M Levitt,et al.  Quantification of the hydrophobic interaction by simulations of the aggregation of small hydrophobic solutes in water , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  I. Robinson,et al.  How water meets a hydrophobic surface. , 2005, Physical review letters.

[32]  F. Gai,et al.  Infrared study of the stability and folding kinetics of a 15-residue beta-hairpin. , 2003, Journal of the American Chemical Society.

[33]  R. Friesner,et al.  Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides† , 2001 .

[34]  Vijay S Pande,et al.  Trp zipper folding kinetics by molecular dynamics and temperature-jump spectroscopy , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[35]  C. Chothia,et al.  Hydrophobic bonding and accessible surface area in proteins , 1974, Nature.

[36]  B Honig,et al.  Reconciling the magnitude of the microscopic and macroscopic hydrophobic effects. , 1991, Science.

[37]  Jiang Zhu,et al.  Parametrization of a Generalized Born/Solvent-Accessible Surface Area Model and Applications to the Simulation of Protein Dynamics , 2002 .

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

[39]  A. Pohorille,et al.  An information theory model of hydrophobic interactions. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[40]  R. Berry,et al.  The origin of long-range attraction between hydrophobes in water. , 2007, Biophysical journal.

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

[42]  Chandler,et al.  Effect of environment on hydrogen bond dynamics in liquid water. , 1996, Physical review letters.

[43]  H. Berendsen,et al.  An extended sampling of the configurational space of HPr from E. coli , 1996, Proteins.

[44]  S. Dixit,et al.  Molecular segregation observed in a concentrated alcohol–water solution , 2002, Nature.

[45]  T. Straatsma,et al.  THE MISSING TERM IN EFFECTIVE PAIR POTENTIALS , 1987 .

[46]  A. Soper,et al.  Decreased structure on dissolving methane in water , 2005 .

[47]  D. Kirschner,et al.  Polypeptide chain folding in the hydrophobic core of hamster scrapie prion: analysis by X-ray diffraction. , 1998, Journal of structural biology.

[48]  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.

[49]  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.

[50]  J. Andrew McCammon,et al.  The structure of liquid water at an extended hydrophobic surface , 1984 .

[51]  H. Berendsen,et al.  Essential dynamics of proteins , 1993, Proteins.

[52]  J. H. R. Clarke,et al.  A comparison of constant energy, constant temperature and constant pressure ensembles in molecular dynamics simulations of atomic liquids , 1984 .

[53]  Anthony K. Felts,et al.  Free Energy Surfaces of -Hairpin and -Helical Peptides Generated by Replica Exchange Molecular Dynamics with the AGBNP Implicit Solvent Model , 2004 .

[54]  H. Scheraga,et al.  Hydration of Inert Solutes. A Molecular Dynamics Study , 1982 .

[55]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[56]  W. C. Still,et al.  The GB/SA Continuum Model for Solvation. A Fast Analytical Method for the Calculation of Approximate Born Radii , 1997 .

[57]  F E Cohen,et al.  Prion protein peptides induce alpha-helix to beta-sheet conformational transitions. , 1995, Biochemistry.

[58]  M. Karplus,et al.  Solution conformations and thermodynamics of structured peptides: molecular dynamics simulation with an implicit solvation model. , 1998, Journal of molecular biology.

[59]  Frank H. Stillinger,et al.  Structure in aqueous solutions of nonpolar solutes from the standpoint of scaled-particle theory , 1973 .