Mapping transiently formed and sparsely populated conformations on a complex energy landscape
- University of Copenhagen, Denmark
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
Kresten Lindorff-Larsen
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.
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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Mapping transiently formed and sparsely populated conformations on a complex energy landscape
eLife 5:e17505.
https://doi.org/10.7554/eLife.17505
