Understanding the roles of amino acid residues in tertiary structure formation of chignolin by using molecular dynamics simulation

Chignolin is a 10‐residue peptide (GYDPETGTWG) that forms a stable β‐hairpin structure in water. However, its design template, GPM12 (GYDDATKTFG), does not have a specific structure. To clarify which amino acids give it the ability to form the β‐hairpin structure, we calculated the folding free‐energy landscapes of chignolin, GPM12, and their chimeric peptides using multicanonical molecular dynamics (MD) simulation. Cluster analysis of the conformational ensembles revealed that the native structure of chignolin was the lowest in terms of free energy while shallow local minima were widely distributed in the free energy landscape of GPM12, in agreement with experimental observations. Among the chimeric peptides, GPM12(D4P/K7G) stably formed the same β‐hairpin structure as that of chignolin in the MD simulation. This was confirmed by nuclear magnetic resonance (NMR) spectroscopy. A comparison of the free‐energy landscapes showed that the conformational distribution of the Asp3‐Pro4 sequence was inherently biased in a way that is advantageous both to forming hydrogen bonds with another β‐strand and to initiating loop structure. In addition, Gly7 helps stabilize the loop structure by having a left‐handed α‐helical conformation. Such a conformation is necessary to complete the loop structure, although it is not preferred by other amino acids. Our results suggest that the consistency between the short‐range interactions that determine the local geometries and the long‐range interactions that determine the global structure is important for stable tertiary structure formation. Proteins 2008. © 2008 Wiley‐Liss, Inc.

[1]  Makoto Taiji,et al.  Folding Dynamics of 10‐Residue β‐Hairpin Peptide Chignolin , 2007 .

[2]  Y. Duan,et al.  Folding free-energy landscape of villin headpiece subdomain from molecular dynamics simulations , 2007, Proceedings of the National Academy of Sciences.

[3]  Yuko Okamoto,et al.  Cooperative folding mechanism of a β‐hairpin peptide studied by a multicanonical replica‐exchange molecular dynamics simulation , 2006, Proteins.

[4]  Martin Zacharias,et al.  Enhanced sampling of peptide and protein conformations using replica exchange simulations with a peptide backbone biasing‐potential , 2006, Proteins.

[5]  David van der Spoel,et al.  Protein folding kinetics and thermodynamics from atomistic simulations. , 2006, Physical review letters.

[6]  Kentaro Shimizu,et al.  Folding free‐energy landscape of a 10‐residue mini‐protein, chignolin , 2006, FEBS letters.

[7]  Chin-Kun Hu,et al.  Free energy landscape and folding mechanism of a β‐hairpin in explicit water: A replica exchange molecular dynamics study , 2005, Proteins.

[8]  M. Seibert,et al.  Reproducible polypeptide folding and structure prediction using molecular dynamics simulations. , 2005, Journal of molecular biology.

[9]  Guoli Wang,et al.  PISCES: recent improvements to a PDB sequence culling server , 2005, Nucleic Acids Res..

[10]  Eric J. Sorin,et al.  How well can simulation predict protein folding kinetics and thermodynamics? , 2005, Annual review of biophysics and biomolecular structure.

[11]  Motonori Ota,et al.  Phylogeny of protein-folding trajectories reveals a unique pathway to native structure. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Shinya Honda,et al.  10 residue folded peptide designed by segment statistics. , 2004, Structure.

[13]  Shugo Nakamura,et al.  Improvement of accuracy of free-energy landscapes of peptides calculated with generalized Born model by using numerical solutions of Poisson’s equation , 2004 .

[14]  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.

[15]  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.

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

[17]  R. Zhou.  Trp-cage: Folding free energy landscape in explicit water , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Hofrichter,et al.  Experimental tests of villin subdomain folding simulations. , 2003, Journal of molecular biology.

[19]  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.

[20]  Shibasish Chowdhury,et al.  Ab initio folding simulation of the Trp-cage mini-protein approaches NMR resolution. , 2003, Journal of molecular biology.

[21]  Tohru Terada,et al.  A method for evaluating multicanonical potential function without iterative refinement: Application to conformational sampling of a globular protein in water , 2003 .

[22]  V. Pande,et al.  Multiplexed-replica exchange molecular dynamics method for protein folding simulation. , 2003, Biophysical journal.

[23]  V. Pande,et al.  The Trp cage: folding kinetics and unfolded state topology via molecular dynamics simulations. , 2002, Journal of the American Chemical Society.

[24]  V. Pande,et al.  Absolute comparison of simulated and experimental protein-folding dynamics , 2002, Nature.

[25]  A. Roitberg,et al.  Smaller and faster: the 20-residue Trp-cage protein folds in 4 micros. , 2002, Journal of the American Chemical Society.

[26]  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.

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

[28]  J. W. Neidigh,et al.  Designing a 20-residue protein , 2002, Nature Structural Biology.

[29]  A. Fersht,et al.  Protein Folding and Unfolding at Atomic Resolution , 2002, Cell.

[30]  B. Berne,et al.  The free energy landscape for β hairpin folding in explicit water , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  N. Skelton,et al.  Tryptophan zippers: Stable, monomeric β-hairpins , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[32]  K. Sanbonmatsu,et al.  Exploring the energy landscape of a β hairpin in explicit solvent , 2001 .

[33]  A Mitsutake,et al.  Generalized-ensemble algorithms for molecular simulations of biopolymers. , 2000, Biopolymers.

[34]  Junmei Wang,et al.  How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? , 2000, J. Comput. Chem..

[35]  G. Schulz,et al.  The structure of adrenodoxin reductase of mitochondrial P450 systems: electron transfer for steroid biosynthesis. , 1999, Journal of molecular biology.

[36]  R J Read,et al.  Crystallography & NMR system: A new software suite for macromolecular structure determination. , 1998, Acta crystallographica. Section D, Biological crystallography.

[37]  M. Struthers,et al.  Design and NMR analyses of compact, independently folded BBA motifs. , 1998, Folding & design.

[38]  A. Kidera,et al.  Multicanonical Ensemble Generated by Molecular Dynamics Simulation for Enhanced Conformational Sampling of Peptides , 1997 .

[39]  J. Thornton,et al.  AQUA and PROCHECK-NMR: Programs for checking the quality of protein structures solved by NMR , 1996, Journal of biomolecular NMR.

[40]  Y. Okamoto,et al.  Molecular dynamics, Langevin, and hybrid Monte Carlo simulations in multicanonical ensemble , 1996, physics/9710018.

[41]  P S Kim,et al.  A thermostable 35-residue subdomain within villin headpiece. , 1996, Journal of molecular biology.

[42]  L. Serrano,et al.  A short linear peptide that folds into a native stable β-hairpin in aqueous solution , 1994, Nature Structural Biology.

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

[44]  P. Kraulis.  A program to produce both detailed and schematic plots of protein structures , 1991 .

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

[46]  B. L. Sibanda,et al.  Conformation of beta-hairpins in protein structures. A systematic classification with applications to modelling by homology, electron density fitting and protein engineering. , 1989, Journal of molecular biology.

[47]  Alan M. Ferrenberg,et al.  New Monte Carlo technique for studying phase transitions. , 1988, Physical review letters.

[48]  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.

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

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

[51]  Robert F. Ling,et al.  Cluster analysis algorithms for data reduction and classification of objects , 1981 .

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

[53]  A. Kidera,et al.  Generalized form of the conserved quantity in constant-temperature molecular dynamics , 2002 .

[54]  D. Case,et al.  Theory and applications of the generalized born solvation model in macromolecular simulations , 2000, Biopolymers.

[55]  N. Go.  The consistency principle in protein structure and pathways of folding. , 1984, Advances in biophysics.