Native topology or specific interactions: what is more important for protein folding?

Fifty-five molecular dynamics runs of two three-stranded antiparallel beta-sheet peptides were performed to investigate the relative importance of amino acid sequence and native topology. The two peptides consist of 20 residues each and have a sequence identity of 15 %. One peptide has Gly-Ser (GS) at both turns, while the other has d-Pro-Gly ((D)PG). The simulations successfully reproduce the NMR solution conformations, irrespective of the starting structure. The large number of folding events sampled along the trajectories at 360 K (total simulation time of about 5 micros) yield a projection of the free-energy landscape onto two significant progress variables. The two peptides have compact denatured states, similar free-energy surfaces, and folding pathways that involve the formation of a beta-hairpin followed by consolidation of the unstructured strand. For the GS peptide, there are 33 folding events that start by the formation of the 2-3 beta-hairpin and 17 with first the 1-2 beta-hairpin. For the (D)PG peptide, the statistical predominance is opposite, 16 and 47 folding events start from the 2-3 beta-hairpin and the 1-2 beta-hairpin, respectively. These simulation results indicate that the overall shape of the free-energy surface is defined primarily by the native-state topology, in agreement with an ever-increasing amount of experimental and theoretical evidence, while the amino acid sequence determines the statistically predominant order of the events.

[1]  M. Karplus,et al.  Use of quantitative structure‐property relationships to predict the folding ability of model proteins , 1998, Proteins.

[2]  M. Karplus,et al.  Effective energy function for proteins in solution , 1999, Proteins.

[3]  A Caflisch,et al.  Acid and thermal denaturation of barnase investigated by molecular dynamics simulations. , 1995, Journal of molecular biology.

[4]  D Baker,et al.  Long-range order in the src SH3 folding transition state. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J. Apostolakis,et al.  Thermodynamics and Kinetics of Folding of Two Model Peptides Investigated by Molecular Dynamics Simulations , 2000 .

[6]  E I Shakhnovich,et al.  Specific nucleus as the transition state for protein folding: evidence from the lattice model. , 1994, Biochemistry.

[7]  K. Dill,et al.  Cooperativity in protein-folding kinetics. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[8]  C. Brooks,et al.  Folding Free Energy Surface of a Three-Stranded β-Sheet Protein , 1999 .

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

[10]  M. Karplus,et al.  Understanding beta-hairpin formation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  T. Lazaridis,et al.  Understanding b-hairpin formation , 1999 .

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

[13]  Amedeo Caflisch,et al.  Free Energy Surface of the Helical Peptide Y(MEARA)6 , 2000 .

[14]  D. Case,et al.  Molecular Dynamics Simulations of Nucleic Acids with a Generalized Born Solvation Model , 2000 .

[15]  Lorna J. Smith,et al.  Understanding protein folding via free-energy surfaces from theory and experiment. , 2000, Trends in biochemical sciences.

[16]  M. Karplus,et al.  Protein Folding: A Perspective from Theory and Experiment , 1998 .

[17]  Scheunert.  Hunger und Unterernährung. Eine biologische und soziologische Studie von s. Morgulis. Berlin 1923. Verlag J. Springer , 1924 .

[18]  V S Pande,et al.  Molecular dynamics simulations of unfolding and refolding of a beta-hairpin fragment of protein G. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  X. Daura,et al.  Folding–unfolding thermodynamics of a β‐heptapeptide from equilibrium simulations , 1999, Proteins.

[20]  J. Thornton,et al.  A revised set of potentials for beta-turn formation in proteins. , 1994, Protein science : a publication of the Protein Society.

[21]  L. Serrano,et al.  The design of linear peptides that fold as monomeric beta-sheet structures. , 1999, Current opinion in structural biology.

[22]  M. Searle,et al.  Structure, folding, and energetics of cooperative interactions between the beta-strands of a de novo sesigned three-stranded antiparallel beta-sheet peptide , 2000 .

[23]  A. Caflisch,et al.  Folding simulations of a three-stranded antiparallel β-sheet peptide , 2000 .

[24]  T. Creighton,et al.  Protein Folding , 1992 .

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

[26]  S. Gellman,et al.  Use of a Designed Triple-Stranded Antiparallel β-Sheet To Probe β-Sheet Cooperativity in Aqueous Solution , 1998 .

[27]  B. Imperiali,et al.  Uniquely folded mini-protein motifs. , 2008, The journal of peptide research : official journal of the American Peptide Society.

[28]  C L Brooks,et al.  Calculations on folding of segment B1 of streptococcal protein G. , 1998, Journal of molecular biology.

[29]  W. F. Gunsteren,et al.  β-Hairpin stability and folding: Molecular dynamics studies of the first β-hairpin of tendamistat , 2000 .

[30]  A Caflisch,et al.  Computer simulations of protein folding by targeted molecular dynamics , 2000, Proteins.

[31]  D Baker,et al.  Critical role of beta-hairpin formation in protein G folding. , 2000, Nature structural biology.

[32]  A. D. McLachlan,et al.  Solvation energy in protein folding and binding , 1986, Nature.

[33]  Luis Serrano,et al.  The folding transition state between SH3 domains is conformationally restricted and evolutionarily conserved , 1999, Nature Structural Biology.

[34]  M Karplus,et al.  The fundamentals of protein folding: bringing together theory and experiment. , 1999, Current opinion in structural biology.

[35]  D. Baker,et al.  Contact order, transition state placement and the refolding rates of single domain proteins. , 1998, Journal of molecular biology.

[36]  V. Muñoz,et al.  Folding dynamics and mechanism of β-hairpin formation , 1997, Nature.

[37]  L A Mirny,et al.  How evolution makes proteins fold quickly. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A Caflisch,et al.  Molecular dynamics simulation of protein denaturation: solvation of the hydrophobic cores and secondary structure of barnase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[39]  K. Dill,et al.  Protein core assembly processes , 1993 .

[40]  A. H. Wang,et al.  Molecular Dynamics Simulations of Three-Strand β-Sheet Folding , 2000 .

[41]  M Karplus,et al.  The folding mechanism of larger model proteins: role of native structure. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[42]  D. Baker,et al.  A surprising simplicity to protein folding , 2000, Nature.

[43]  L. Mirny,et al.  Universally conserved positions in protein folds: reading evolutionary signals about stability, folding kinetics and function. , 1999, Journal of molecular biology.

[44]  E. Shakhnovich,et al.  A strategy for detecting the conservation of folding-nucleus residues in protein superfamilies. , 1998, Folding & design.

[45]  L. Serrano,et al.  The design of linear peptides that fold as monomeric β-sheet structures , 1999 .

[46]  M. Karplus,et al.  Solution Conformation and Thermodynamics of Structured Peptides: Molecular Dynamics Simulation with , 1998 .

[47]  M. Jiménez,et al.  De novo design of a monomeric three‐stranded antiparallel β‐sheet , 2008, Protein science : a publication of the Protein Society.

[48]  W. C. Still,et al.  A rapid approximation to the solvent accessible surface areas of atoms , 1988 .

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

[50]  M. Gruebele,et al.  Mapping the transition state of the WW domain β-sheet , 2000 .

[51]  S. Gellman,et al.  Rules for Antiparallel β-Sheet Design: d-Pro-Gly Is Superior to l-Asn-Gly for β-Hairpin Nucleation1 , 1998 .