Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations

Thukral, Lipi; Daidone, Isabella; Smith, Jeremy C.

doi:10.1371/journal.pcbi.1002137

Title: Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations

Journal Article · Thu Sep 08 00:00:00 EDT 2011 · PLoS Computational Biology (Online)

DOI:https://doi.org/10.1371/journal.pcbi.1002137· OSTI ID:1627213

Thukral, Lipi ^[1]; Daidone, Isabella ^[2]; Smith, Jeremy C. ^[3]

Univ. of Heidelberg (Germany). Interdisciplinary Center for Scientific Computing
Univ. of L’Aquila, Coppito (Italy). Dept. of Chemistry, Chemical Engineering and Materials
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Molecular Biophysics

Small globular proteins and peptides commonly exhibit two-state folding kinetics in which the rate limiting step of folding is the surmounting of a single free energy barrier at the transition state (TS) separating the folded and the unfolded states. An intriguing question is whether the polypeptide chain reaches, and leaves, the TS by completely random fluctuations, or whether there is a directed, stepwise process. Here, the folding TS of a 15-residue b-hairpin peptide, Peptide 1, is characterized using independent 2.5 μs-long unbiased atomistic molecular dynamics (MD) simulations (a total of 15 μs). The trajectories were started from fully unfolded structures. Multiple (spontaneous) folding events to the NMR-derived conformation are observed, allowing both structural and dynamical characterization of the folding TS. A common loop-like topology is observed in all the TS structures with native end-to-end and turn contacts, while the central segments of the strands are not in contact. Non-native sidechain contacts are present in the TS between the only tryptophan (W11) and the turn region (P7-G9). Prior to the TS the turn is found to be already locked by the W11 sidechain, while the ends are apart. Once the ends have also come into contact, the TS is reached. Finally, along the reactive folding paths the cooperative loss of the W11 non-native contacts and the formation of the central inter-strand native contacts lead to the peptide rapidly proceeding from the TS to the native state. The present results indicate a directed stepwise process to folding the peptide.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; USDOE Laboratory Directed Research and Development (LDRD) Program; German Research Foundation (DFG)

Grant/Contract Number:: AC05-00OR22725; SM 63/12-1

OSTI ID:: 1627213

Journal Information:: PLoS Computational Biology (Online), Vol. 7, Issue 9; ISSN 1553-7358

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

References (57)

On the transition coordinate for protein folding Du, Rose; Pande, Vijay S.; Grosberg, Alexander Yu. The Journal of Chemical Physics, Vol. 108, Issue 1 https://doi.org/10.1063/1.475393	journal	January 1998
Structure-activity relationships in engineered proteins: analysis of use of binding energy by linear free energy relationships Fersht, Alan R.; Leatherbarrow, Robin J.; Wells, Tim N. C. Biochemistry, Vol. 26, Issue 19 https://doi.org/10.1021/bi00393a013	journal	September 1987
Structure of the Transition State for Folding of a Protein Derived from Experiment and Simulation Daggett, Valerie; Li, Aijun; Itzhaki, Laura S. Journal of Molecular Biology, Vol. 257, Issue 2 https://doi.org/10.1006/jmbi.1996.0173	journal	March 1996
Improved Gō-like Models Demonstrate the Robustness of Protein Folding Mechanisms Towards Non-native Interactions Karanicolas, John; Brooks, Charles L. Journal of Molecular Biology, Vol. 334, Issue 2 https://doi.org/10.1016/j.jmb.2003.09.047	journal	November 2003
Is there a unifying mechanism for protein folding? Daggett, Valerie; Fersht, Alan R. Trends in Biochemical Sciences, Vol. 28, Issue 1 https://doi.org/10.1016/S0968-0004(02)00012-9	journal	January 2003
GROMACS: Fast, flexible, and free Van Der Spoel, David; Lindahl, Erik; Hess, Berk Journal of Computational Chemistry, Vol. 26, Issue 16 https://doi.org/10.1002/jcc.20291	journal	January 2005
T RANSITION P ATH S AMPLING : Throwing Ropes Over Rough Mountain Passes, in the Dark Bolhuis, Peter G.; Chandler, David; Dellago, Christoph Annual Review of Physical Chemistry, Vol. 53, Issue 1 https://doi.org/10.1146/annurev.physchem.53.082301.113146	journal	October 2002
Determination of the Transition State Ensemble for the Folding of Ubiquitin from a Combination of Φ and Ψ Analyses Várnai, Péter; Dobson, Christopher M.; Vendruscolo, Michele Journal of Molecular Biology, Vol. 377, Issue 2 https://doi.org/10.1016/j.jmb.2008.01.012	journal	March 2008
The Structure of the Transition State for Folding of Chymotrypsin Inhibitor 2 Analysed by Protein Engineering Methods: Evidence for a Nucleation-condensation Mechanism for Protein Folding Itzhaki, Laura S.; Otzen, Daniel E.; Fersht, Alan R. Journal of Molecular Biology, Vol. 254, Issue 2 https://doi.org/10.1006/jmbi.1995.0616	journal	November 1995
A comparison of constant energy, constant temperature and constant pressure ensembles in molecular dynamics simulations of atomic liquids Brown, D.; Clarke, J. H. R. Molecular Physics, Vol. 51, Issue 5 https://doi.org/10.1080/00268978400100801	journal	April 1984
Transition-path sampling of -hairpin folding Bolhuis, P. G. Proceedings of the National Academy of Sciences, Vol. 100, Issue 21 https://doi.org/10.1073/pnas.1534924100	journal	October 2003
Mapping the Folding Pathway of an Immunoglobulin Domain Fowler, Susan B.; Clarke, Jane Structure, Vol. 9, Issue 5 https://doi.org/10.1016/S0969-2126(01)00596-2	journal	May 2001
Comparison of simple potential functions for simulating liquid water Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D. The Journal of Chemical Physics, Vol. 79, Issue 2 https://doi.org/10.1063/1.445869	journal	July 1983
Transition state heterogeneity in GCN4 coiled coil folding studied by using multisite mutations and crosslinking Moran, L. B.; Schneider, J. P.; Kentsis, A. Proceedings of the National Academy of Sciences, Vol. 96, Issue 19 https://doi.org/10.1073/pnas.96.19.10699	journal	September 1999
Critical role of β-hairpin formation in protein G folding McCallister, Erika L.; Alm, Eric; Baker, David Nature Structural Biology, Vol. 7, Issue 8, p. 669-673 https://doi.org/10.1038/77971	journal	August 2000
Three key residues form a critical contact network in a protein folding transition state Vendruscolo, Michele; Paci, Emanuele; Dobson, Christopher M. Nature, Vol. 409, Issue 6820 https://doi.org/10.1038/35054591	journal	February 2001
Determination of the folding transition states of barnase by using I-value-restrained simulations validated by double mutant IJ-values Salvatella, X.; Dobson, C. M.; Fersht, A. R. Proceedings of the National Academy of Sciences, Vol. 102, Issue 35 https://doi.org/10.1073/pnas.0408226102	journal	August 2005
Dimerization of the p53 Oligomerization Domain: Identification of a Folding Nucleus by Molecular Dynamics Simulations Chong, Lillian T.; Snow, Christopher D.; Rhee, Young Min Journal of Molecular Biology, Vol. 345, Issue 4 https://doi.org/10.1016/j.jmb.2004.10.083	journal	January 2005
P versus Q: Structural reaction coordinates capture protein folding on smooth landscapes Cho, S. S.; Levy, Y.; Wolynes, P. G. Proceedings of the National Academy of Sciences, Vol. 103, Issue 3 https://doi.org/10.1073/pnas.0509768103	journal	January 2006
Analysis and prediction of the different types of β-turn in proteins Wilmot, C. M.; Thornton, J. M. Journal of Molecular Biology, Vol. 203, Issue 1 https://doi.org/10.1016/0022-2836(88)90103-9	journal	September 1988
Cooperativity in two-state protein folding kinetics Weikl, T. R. Protein Science, Vol. 13, Issue 3 https://doi.org/10.1110/ps.03403604	journal	February 2004
Common Folding Mechanism of a β-Hairpin Peptide via Non-native Turn Formation Revealed by Unbiased Molecular Dynamics Simulations Thukral, Lipi; Smith, Jeremy C.; Daidone, Isabella Journal of the American Chemical Society, Vol. 131, Issue 50 https://doi.org/10.1021/ja9064365	journal	November 2009
Lattice models for proteins reveal multiple folding nuclei for nucleation-collapse mechanism 1 1Edited by A. R. Fersht Klimov, D. K.; Thirumalai, D. Journal of Molecular Biology, Vol. 282, Issue 2 https://doi.org/10.1006/jmbi.1998.1997	journal	September 1998
Specific Nucleus as the Transition State for Protein Folding: Evidence from the Lattice Model Abkevich, V. I.; Gutin, A. M.; Shakhnovich, E. I. Biochemistry, Vol. 33, Issue 33 https://doi.org/10.1021/bi00199a029	journal	August 1994
Transition-state structure as a unifying basis in protein-folding mechanisms: Contact order, chain topology, stability, and the extended nucleus mechanism Fersht, A. R. Proceedings of the National Academy of Sciences, Vol. 97, Issue 4 https://doi.org/10.1073/pnas.97.4.1525	journal	February 2000
Infrared Study of the Stability and Folding Kinetics of a 15-Residue β -Hairpin Xu, Yao; Oyola, Rolando; Gai, Feng Journal of the American Chemical Society, Vol. 125, Issue 50 https://doi.org/10.1021/ja037053b	journal	November 2003
Multiple protein folding nuclei and the transition state ensemble in two-state proteins Klimov, D. K.; Thirumalai, D. Proteins: Structure, Function, and Genetics, Vol. 43, Issue 4 https://doi.org/10.1002/prot.1058	journal	January 2001
Folding Time Predictions from All-atom Replica Exchange Simulations Yang, Sichun; Onuchic, José N.; García, Angel E. Journal of Molecular Biology, Vol. 372, Issue 3 https://doi.org/10.1016/j.jmb.2007.07.010	journal	September 2007
LINCS: A linear constraint solver for molecular simulations Hess, Berk; Bekker, Henk; Berendsen, Herman J. C. Journal of Computational Chemistry, Vol. 18, Issue 12 https://doi.org/10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H	journal	September 1997
Protein folding and stability: the pathway of folding of barnase Fersht, Alan R. FEBS Letters, Vol. 325, Issue 1-2 https://doi.org/10.1016/0014-5793(93)81405-O	journal	June 1993
Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems Darden, Tom; York, Darrin; Pedersen, Lee The Journal of Chemical Physics, Vol. 98, Issue 12 https://doi.org/10.1063/1.464397	journal	June 1993
Folding pathway of a lattice model for proteins Pande, V. S.; Rokhsar, D. S. Proceedings of the National Academy of Sciences, Vol. 96, Issue 4 https://doi.org/10.1073/pnas.96.4.1273	journal	February 1999
Molecular dynamics simulations from putative transition states of α-spectrin SH3 domain Periole, Xavier; Vendruscolo, Michele; Mark, Alan E. Proteins: Structure, Function, and Bioinformatics, Vol. 69, Issue 3 https://doi.org/10.1002/prot.21491	journal	July 2007
Can protein unfolding simulate protein folding? Finkelstein, A. V. Protein Engineering Design and Selection, Vol. 10, Issue 8 https://doi.org/10.1093/protein/10.8.843	journal	August 1997
Redesigning enzyme structure by site-directed mutagenesis: tyrosyl tRNA synthetase and ATP binding Winter, Greg; Fersht, Alan R.; Wilkinson, Anthony J. Nature, Vol. 299, Issue 5885 https://doi.org/10.1038/299756a0	journal	October 1982
The present view of the mechanism of protein folding Daggett, Valerie; Fersht, Alan Nature Reviews Molecular Cell Biology, Vol. 4, Issue 6 https://doi.org/10.1038/nrm1126	journal	June 2003
Molecular dynamics simulations of protein folding from the transition state Gsponer, J.; Caflisch, A. Proceedings of the National Academy of Sciences, Vol. 99, Issue 10 https://doi.org/10.1073/pnas.092686399	journal	April 2002
Protein folding roller coaster, one molecule at a time Shakhnovich, E. Proceedings of the National Academy of Sciences, Vol. 106, Issue 29 https://doi.org/10.1073/pnas.0906228106	journal	July 2009
The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin Jorgensen, William L.; Tirado-Rives, Julian Journal of the American Chemical Society, Vol. 110, Issue 6 https://doi.org/10.1021/ja00214a001	journal	March 1988
Reconstruction of the src-SH3 Protein Domain Transition State Ensemble using Multiscale Molecular Dynamics Simulations Ding, Feng; Guo, Weihua; Dokholyan, Nikolay V. Journal of Molecular Biology, Vol. 350, Issue 5 https://doi.org/10.1016/j.jmb.2005.05.017	journal	July 2005
-Value analysis by molecular dynamics simulations of reversible folding Settanni, G.; Rao, F.; Caflisch, A. Proceedings of the National Academy of Sciences, Vol. 102, Issue 3 https://doi.org/10.1073/pnas.0406754102	journal	January 2005
Computing the transition state populations in simple protein models Ozkan, S. Banu; Dill, Ken A.; Bahar, Ivet Biopolymers, Vol. 68, Issue 1 https://doi.org/10.1002/bip.10280	journal	December 2002
Identifying the protein folding nucleus using molecular dynamics 1 1Edited by A. R. Fersht Dokholyan, Nikolay V.; Buldyrev, Sergey V.; Stanley, H. Eugene Journal of Molecular Biology, Vol. 296, Issue 5 https://doi.org/10.1006/jmbi.1999.3534	journal	March 2000
The ensemble folding kinetics of protein G from an all-atom Monte Carlo simulation Shimada, J.; Shakhnovich, E. I. Proceedings of the National Academy of Sciences, Vol. 99, Issue 17 https://doi.org/10.1073/pnas.162268099	journal	August 2002
Nucleation and the Transition State of the SH3 Domain Hubner, Isaac A.; Edmonds, Katherine A.; Shakhnovich, Eugene I. Journal of Molecular Biology, Vol. 349, Issue 2 https://doi.org/10.1016/j.jmb.2005.03.050	journal	June 2005
13Cα and 13Cβ chemical shifts as a tool to delineate β-hairpin structures in peptides Santiveri, Clara M.; Rico, Manuel; Jiménez, M. Angeles Journal of Biomolecular NMR, Vol. 19, Issue 4, p. 331-345 https://doi.org/10.1023/A:1011224625129	journal	January 2001
Is protein unfolding the reverse of protein folding? A lattice simulation analysis 1 1Edited by A. R. Fersht Dinner, Aaron R.; Karplus, Martin Journal of Molecular Biology, Vol. 292, Issue 2 https://doi.org/10.1006/jmbi.1999.3051	journal	September 1999
Commitment and Nucleation in the Protein G Transition State Hubner, Isaac A.; Shimada, Jun; Shakhnovich, Eugene I. Journal of Molecular Biology, Vol. 336, Issue 3 https://doi.org/10.1016/j.jmb.2003.12.032	journal	February 2004
Simulations of the role of water in the protein-folding mechanism Rhee, Y. M.; Sorin, E. J.; Jayachandran, G. Proceedings of the National Academy of Sciences, Vol. 101, Issue 17 https://doi.org/10.1073/pnas.0307898101	journal	April 2004
Probing the folding free energy landscape of the src-SH3 protein domain Shea, J. -E.; Onuchic, J. N.; Brooks, C. L. Proceedings of the National Academy of Sciences, Vol. 99, Issue 25 https://doi.org/10.1073/pnas.242293099	journal	November 2002
Transition states for protein folding have native topologies despite high structural variability Lindorff-Larsen, Kresten; Vendruscolo, Michele; Paci, Emanuele Nature Structural & Molecular Biology, Vol. 11, Issue 5 https://doi.org/10.1038/nsmb765	journal	April 2004
Parallel Folding Pathways in the SH3 Domain Protein Lam, A. R.; Borreguero, J. M.; Ding, F. Journal of Molecular Biology, Vol. 373, Issue 5 https://doi.org/10.1016/j.jmb.2007.08.032	journal	November 2007
The Protein Folding Network Rao, Francesco; Caflisch, Amedeo Journal of Molecular Biology, Vol. 342, Issue 1 https://doi.org/10.1016/j.jmb.2004.06.063	journal	September 2004
Direct Molecular Dynamics Observation of Protein Folding Transition State Ensemble Ding, Feng; Dokholyan, Nikolay V.; Buldyrev, Sergey V. Biophysical Journal, Vol. 83, Issue 6 https://doi.org/10.1016/s0006-3495(02)75352-6	journal	December 2002
Surfing on protein folding energy landscapes Schymkowitz, Joost W. H.; Rousseau, Frederic; Serrano, Luis Proceedings of the National Academy of Sciences, Vol. 99, Issue 25 https://doi.org/10.1073/pnas.012686599	journal	December 2002
Experimental determination of upper bound for transition path times in protein folding from single-molecule photon-by-photon trajectories Chung, H. S.; Louis, J. M.; Eaton, W. A. Proceedings of the National Academy of Sciences, Vol. 106, Issue 29 https://doi.org/10.1073/pnas.0901178106	journal	July 2009
Modelling protein unfolding: hen egg-white lysozyme Williams, M. A.; Thornton, J. M.; Goodfellow, J. M. Protein Engineering Design and Selection, Vol. 10, Issue 8 https://doi.org/10.1093/protein/10.8.895	journal	August 1997

Cited By (1)

Turn-Directed α-β Conformational Transition of α-syn12 Peptide at Different pH Revealed by Unbiased Molecular Dynamics Simulations Liu, Lei; Cao, Zanxia International Journal of Molecular Sciences, Vol. 14, Issue 6 https://doi.org/10.3390/ijms140610896	journal	May 2013

Similar Records

Denaturant-Dependent Conformational Changes in a [beta]-Trefoil Protein: Global and Residue-Specific Aspects of an Equilibrium Denaturation Process

Journal Article · Tue Jan 12 00:00:00 EST 2010 · Biochemistry-US · OSTI ID:1627213

Latypov, Ramil F; Liu, Dingjiang; Jacob, Jaby; +5 more

Frustration and folding of a TIM barrel protein

Journal Article · Thu Jul 25 00:00:00 EDT 2019 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1627213

Halloran, Kevin T.; Wang, Yanming; Arora, Karunesh; +5 more

Structure of an RNA dimer of a regulatory element from human thymidylate synthase mRNA

Journal Article · Tue Sep 27 00:00:00 EDT 2011 · Acta Crystallogr. D · OSTI ID:1627213

Dibrov, Sergey; McLean, Jaime; Hermann, Thomas

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Biochemistry & Molecular Biology
Mathematical & Computational Biology

Title: Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations

Citation Formats

References (57)

Cited By (1)

Similar Records

Related Subjects