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Title: Benchmarking all-atom simulations using hydrogen exchange

Abstract

Molecular dynamics simulations have recently become capable of observing multiple protein unfolding and refolding events in a single-millisecond–long trajectory. This major advance produces atomic-level information with nanosecond resolution, a feat unmatched by experimental methods. Such simulations are being extensively analyzed to assess their description of protein folding, yet the results remain difficult to validate experimentally. We apply a combination of hydrogen exchange, NMR, and other techniques to test the simulations with a resolution of single H-bonds. Several significant discrepancies between the simulations and experimental data were uncovered for regions of the energy surface outside of the native basin. This comparison yields suggestions for improving the force fields and provides a general method for experimentally validating folding simulations.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1400311
Resource Type:
Journal Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 111; Journal Issue: 45; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Skinner, John J., Yu, Wookyung, Gichana, Elizabeth K., Baxa, Michael C., Hinshaw, James R., Freed, Karl F., and Sosnick, Tobin R. Benchmarking all-atom simulations using hydrogen exchange. United States: N. p., 2014. Web. doi:10.1073/pnas.1404213111.
Skinner, John J., Yu, Wookyung, Gichana, Elizabeth K., Baxa, Michael C., Hinshaw, James R., Freed, Karl F., & Sosnick, Tobin R. Benchmarking all-atom simulations using hydrogen exchange. United States. doi:10.1073/pnas.1404213111.
Skinner, John J., Yu, Wookyung, Gichana, Elizabeth K., Baxa, Michael C., Hinshaw, James R., Freed, Karl F., and Sosnick, Tobin R. Mon . "Benchmarking all-atom simulations using hydrogen exchange". United States. doi:10.1073/pnas.1404213111.
@article{osti_1400311,
title = {Benchmarking all-atom simulations using hydrogen exchange},
author = {Skinner, John J. and Yu, Wookyung and Gichana, Elizabeth K. and Baxa, Michael C. and Hinshaw, James R. and Freed, Karl F. and Sosnick, Tobin R.},
abstractNote = {Molecular dynamics simulations have recently become capable of observing multiple protein unfolding and refolding events in a single-millisecond–long trajectory. This major advance produces atomic-level information with nanosecond resolution, a feat unmatched by experimental methods. Such simulations are being extensively analyzed to assess their description of protein folding, yet the results remain difficult to validate experimentally. We apply a combination of hydrogen exchange, NMR, and other techniques to test the simulations with a resolution of single H-bonds. Several significant discrepancies between the simulations and experimental data were uncovered for regions of the energy surface outside of the native basin. This comparison yields suggestions for improving the force fields and provides a general method for experimentally validating folding simulations.},
doi = {10.1073/pnas.1404213111},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 45,
volume = 111,
place = {United States},
year = {2014},
month = {10}
}

Works referenced in this record:

Protein hydrogen exchange: Testing current models
journal, June 2012

  • Skinner, John J.; Lim, Woon K.; Bédard, Sabrina
  • Protein Science, Vol. 21, Issue 7
  • DOI: 10.1002/pro.2082

Barrier-limited, microsecond folding of a stable protein measured with hydrogen exchange: Implications for downhill folding
journal, October 2004

  • Meisner, W. K.; Sosnick, T. R.
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 44
  • DOI: 10.1073/pnas.0404895101

Structural Characterization of λ-Repressor Folding from All-Atom Molecular Dynamics Simulations
journal, April 2012

  • Liu, Yanxin; Strümpfer, Johan; Freddolino, Peter L.
  • The Journal of Physical Chemistry Letters, Vol. 3, Issue 9
  • DOI: 10.1021/jz300017c

Collapse kinetics and chevron plots from simulations of denaturant-dependent folding of globular proteins
journal, April 2011

  • Liu, Z.; Reddy, G.; O'Brien, E. P.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 19
  • DOI: 10.1073/pnas.1019500108

Scoring function for automated assessment of protein structure template quality
journal, January 2004

  • Zhang, Yang; Skolnick, Jeffrey
  • Proteins: Structure, Function, and Bioinformatics, Vol. 57, Issue 4
  • DOI: 10.1002/prot.20264

How do small single-domain proteins fold?
journal, August 1998


Unfolded-State Dynamics and Structure of Protein L Characterized by Simulation and Experiment
journal, April 2010

  • Voelz, Vincent A.; Singh, Vijay R.; Wedemeyer, William J.
  • Journal of the American Chemical Society, Vol. 132, Issue 13
  • DOI: 10.1021/ja908369h

Characterizing the unfolded states of proteins using single-molecule FRET spectroscopy and molecular simulations
journal, January 2007

  • Merchant, K. A.; Best, R. B.; Louis, J. M.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 5
  • DOI: 10.1073/pnas.0607097104

Atomic-Level Characterization of the Structural Dynamics of Proteins
journal, October 2010


Structure and Dynamics of an Unfolded Protein Examined by Molecular Dynamics Simulation
journal, February 2012

  • Lindorff-Larsen, Kresten; Trbovic, Nikola; Maragakis, Paul
  • Journal of the American Chemical Society, Vol. 134, Issue 8
  • DOI: 10.1021/ja209931w

Helix, Sheet, and Polyproline II Frequencies and Strong Nearest Neighbor Effects in a Restricted Coil Library
journal, July 2005

  • Jha, Abhishek K.; Colubri, Andres; Zaman, Muhammad H.
  • Biochemistry, Vol. 44, Issue 28
  • DOI: 10.1021/bi0474822

Fully Reduced Ribonuclease A Does not Expand at High Denaturant Concentration or Temperature
journal, March 2007

  • Jacob, Jaby; Dothager, Robin S.; Thiyagarajan, P.
  • Journal of Molecular Biology, Vol. 367, Issue 3
  • DOI: 10.1016/j.jmb.2007.01.012

How Fast-Folding Proteins Fold
journal, October 2011


Probing the protein-folding mechanism using denaturant and temperature effects on rate constants
journal, September 2013

  • Guinn, E. J.; Kontur, W. S.; Tsodikov, O. V.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 42
  • DOI: 10.1073/pnas.1311948110

Mechanisms and uses of hydrogen exchange
journal, February 1996

  • Englander, S. Walter; Sosnick, Tobin R.; Englander, Joan J.
  • Current Opinion in Structural Biology, Vol. 6, Issue 1
  • DOI: 10.1016/S0959-440X(96)80090-X

Early Collapse is not an Obligate Step in Protein Folding
journal, April 2004

  • Jacob, Jaby; Krantz, Bryan; Dothager, Robin S.
  • Journal of Molecular Biology, Vol. 338, Issue 2
  • DOI: 10.1016/j.jmb.2004.02.065

Simple few-state models reveal hidden complexity in protein folding
journal, July 2012

  • Beauchamp, K. A.; McGibbon, R.; Lin, Y. -S.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 44
  • DOI: 10.1073/pnas.1201810109

Native contacts determine protein folding mechanisms in atomistic simulations
journal, October 2013

  • Best, R. B.; Hummer, G.; Eaton, W. A.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 44
  • DOI: 10.1073/pnas.1311599110

The folding of single domain proteins—have we reached a consensus?
journal, February 2011


Primary structure effects on peptide group hydrogen exchange
journal, September 1993

  • Bai, Yawen; Milne, John S.; Mayne, Leland
  • Proteins: Structure, Function, and Genetics, Vol. 17, Issue 1
  • DOI: 10.1002/prot.340170110

Isotope effects in peptide group hydrogen exchange
journal, September 1993

  • Connelly, Gregory P.; Bai, Yawen; Jeng, Mei-Fen
  • Proteins: Structure, Function, and Genetics, Vol. 17, Issue 1
  • DOI: 10.1002/prot.340170111

The burst phase in ribonuclease A folding and solvent dependence of the unfolded state
journal, October 1998

  • Qi, Phoebe X.; Sosnick, Tobin R.; Englander, S. Walter
  • Nature Structural Biology, Vol. 5, Issue 10
  • DOI: 10.1038/2321

Structure and Stability of Monomeric .lambda. Repressor: NMR Evidence for Two-State Folding
journal, March 1995


The energy landscape of a fast-folding protein mapped by Ala→Gly Substitutions
journal, April 1997

  • Burton, Randall E.; Huang, Guewha S.; Daugherty, Margaret A.
  • Nature Structural Biology, Vol. 4, Issue 4
  • DOI: 10.1038/nsb0497-305

Ultrafast signals in protein folding and the polypeptide contracted state
journal, August 1997

  • Sosnick, T. R.; Shtilerman, M. D.; Mayne, L.
  • Proceedings of the National Academy of Sciences, Vol. 94, Issue 16
  • DOI: 10.1073/pnas.94.16.8545

Specific collapse followed by slow hydrogen-bond formation of  -sheet in the folding of single-chain monellin
journal, February 2005

  • Kimura, T.; Uzawa, T.; Ishimori, K.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 8
  • DOI: 10.1073/pnas.0407982102

Measuring hydrogen exchange rates in invisible protein excited states
journal, June 2014

  • Long, D.; Bouvignies, G.; Kay, L. E.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 24
  • DOI: 10.1073/pnas.1405011111

Native States of Fast-Folding Proteins Are Kinetic Traps
journal, March 2013

  • Dickson, Alex; Brooks, Charles L.
  • Journal of the American Chemical Society, Vol. 135, Issue 12
  • DOI: 10.1021/ja311077u

Do all backbone polar groups in proteins form hydrogen bonds?
journal, July 2005


Protein folding intermediates: native-state hydrogen exchange
journal, July 1995


Hydrogen exchange: The modern legacy of Linderstrøm-Lang
journal, May 1997


Fast and Slow Intermediate Accumulation and the Initial Barrier Mechanism in Protein Folding
journal, November 2002


Random-coil behavior and the dimensions of chemically unfolded proteins
journal, August 2004

  • Kohn, J. E.; Millett, I. S.; Jacob, J.
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 34
  • DOI: 10.1073/pnas.0403643101

To milliseconds and beyond: challenges in the simulation of protein folding
journal, February 2013

  • Lane, Thomas J.; Shukla, Diwakar; Beauchamp, Kyle A.
  • Current Opinion in Structural Biology, Vol. 23, Issue 1
  • DOI: 10.1016/j.sbi.2012.11.002

Assessing the accuracy of physical models used in protein-folding simulations: quantitative evidence from long molecular dynamics simulations
journal, February 2014

  • Piana, Stefano; Klepeis, John L.; Shaw, David E.
  • Current Opinion in Structural Biology, Vol. 24
  • DOI: 10.1016/j.sbi.2013.12.006

Anatomy of energetic changes accompanying urea-induced protein denaturation
journal, September 2007

  • Auton, M.; Holthauzen, L. M. F.; Bolen, D. W.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 39
  • DOI: 10.1073/pnas.0706251104

Small-Angle X-ray Scattering and Single-Molecule FRET Spectroscopy Produce Highly Divergent Views of the Low-Denaturant Unfolded State
journal, May 2012

  • Yoo, Tae Yeon; Meisburger, Steve P.; Hinshaw, James
  • Journal of Molecular Biology, Vol. 418, Issue 3-4
  • DOI: 10.1016/j.jmb.2012.01.016

Protein Vivisection Reveals Elusive Intermediates in Folding
journal, April 2010


Understanding protein hydrogen bond formation with kinetic H/D amide isotope effects
journal, April 2002

  • Krantz, Bryan A.; Srivastava, Alok K.; Nauli, Sehat
  • Nature Structural Biology, Vol. 9, Issue 6
  • DOI: 10.1038/nsb794

Statistical coil model of the unfolded state: Resolving the reconciliation problem
journal, August 2005

  • Jha, A. K.; Colubri, A.; Freed, K. F.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 37
  • DOI: 10.1073/pnas.0506078102

Folding of chymotrypsin inhibitor 2. 1. Evidence for a two-state transition
journal, October 1991


Experiments and simulations show how long-range contacts can form in expanded unfolded proteins with negligible secondary structure
journal, January 2013

  • Meng, W.; Lyle, N.; Luan, B.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 6
  • DOI: 10.1073/pnas.1216979110

Atomic-level description of ubiquitin folding
journal, March 2013

  • Piana, S.; Lindorff-Larsen, K.; Shaw, D. E.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 15
  • DOI: 10.1073/pnas.1218321110

Solution structure of a protein denatured state and folding intermediate
journal, October 2005

  • Religa, T. L.; Markson, J. S.; Mayor, U.
  • Nature, Vol. 437, Issue 7061
  • DOI: 10.1038/nature04054

    Works referencing / citing this record:

    Trajectory-based training enables protein simulations with accurate folding and Boltzmann ensembles in cpu-hours
    journal, December 2018