1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Mapping transiently formed and sparsely populated conformations on a complex energy landscape

  1. Yong Wang
  2. Elena Papaleo
  3. Kresten Lindorff-Larsen  Is a corresponding author
  1. University of Copenhagen, Denmark
Research Article
  • Cited 28
  • Annotations
Cite this article as: eLife 2016;5:e17505 doi: 10.7554/eLife.17505

Abstract

Determining the structures, kinetics, thermodynamics and mechanisms that underlie conformational exchange processes in proteins remains extremely difficult. Only in favourable cases is it possible to provide atomic-level descriptions of sparsely populated and transiently formed alternative conformations. Here we benchmark the ability of enhanced-sampling molecular dynamics simulations to determine the free energy landscape of the L99A cavity mutant of T4 lysozyme. We find that the simulations capture key properties previously measured by NMR relaxation dispersion methods including the structure of a minor conformation, the kinetics and thermodynamics of conformational exchange, and the effect of mutations. We discover a new tunnel that involves the transient exposure towards the solvent of an internal cavity, and show it to be relevant for ligand escape. Together, our results provide a comprehensive view of the structural landscape of a protein, and point forward to studies of conformational exchange in systems that are less characterized experimentally.

Article and author information

Author details

  1. Yong Wang

    Structural Biology and NMR Laboratory, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9156-0377
  2. Elena Papaleo

    Structural Biology and NMR Laboratory, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  3. Kresten Lindorff-Larsen

    Structural Biology and NMR Laboratory, University of Copenhagen, Copenhagen, Denmark
    For correspondence
    lindorff@bio.ku.dk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4750-6039

Funding

Novo Nordisk

  • Kresten Lindorff-Larsen

Carlsbergfondet

  • Kresten Lindorff-Larsen

Danish e-Infrastructure Cooperation

  • Kresten Lindorff-Larsen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Yibing Shan, DE Shaw Research, United States

Publication history

  1. Received: May 4, 2016
  2. Accepted: August 22, 2016
  3. Accepted Manuscript published: August 23, 2016 (version 1)
  4. Version of Record published: October 4, 2016 (version 2)

Copyright

© 2016, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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