ArticleChemical science2016
Atomistic picture of conformational exchange in a T4 lysozyme cavity mutant: an experiment-guided molecular dynamics study.
Article in Chemical science, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Mapping the FF domain folding pathway via structures of transiently populated folding intermediates.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structural dynamics in chromatin unraveling by pioneer transcription factors.Biophysical reviews · 2024Review
- Studying micro to millisecond protein dynamics using simple amideJournal of biomolecular NMR · 2023Article
- Automated Path Searching Reveals the Mechanism of Hydrolysis Enhancement by T4 Lysozyme Mutants.International journal of molecular sciences · 2022Article
- Dynamic regulation of Zn(II) sequestration by calgranulin C.Protein science : a publication of the Protein Society · 2022Article
- Elucidating the mechanisms underlying protein conformational switching using NMR spectroscopy.Journal of magnetic resonance open · 2022Article
- The A39G FF domain folds on a volcano-shaped free energy surface via separate pathways.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Energy penalties enhance flexible receptor docking in a model cavity.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- A suite ofJournal of biomolecular NMR · 2020Article
- A CEST NMR experiment to obtain glycineJournal of biomolecular NMR · 2020Article
- Dynamic design: manipulation of millisecond timescale motions on the energy landscape of cyclophilin A.Chemical science · 2020Article
- The Structural and Functional Diversity of Intrinsically Disordered Regions in Transmembrane Proteins.The Journal of membrane biology · 2019Review
- De Novo Prediction of Binders and Nonbinders for T4 Lysozyme by gREST Simulations.Journal of chemical information and modeling · 2019Article
- On identifying collective displacements in apo-proteins that reveal eventual binding pathways.PLoS computational biology · 2019Article
- A methylJournal of biomolecular NMR · 2018Article
- Atomic resolution mechanism of ligand binding to a solvent inaccessible cavity in T4 lysozyme.PLoS computational biology · 2018Article
- Escape of a Small Molecule from Inside T4 Lysozyme by Multiple Pathways.Biophysical journal · 2018Article
- Measuring the signs of the methylJournal of biomolecular NMR · 2018Article
- Article
- Biomolecular conformational changes and ligand binding: from kinetics to thermodynamics.Chemical science · 2017Article
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Despite the importance of dynamics to protein function there is little information about the states that are formed as the protein explores its conformational landscape or about the mechanism by which transitions between the different states occur. Here we used a combined NMR spin relaxation and unbiased molecular dynamics (MD) approach to investigate the exchange process by which a cavity in an L99A mutant of T4 lysozyme (T4L 99A) interconverts between an empty and occupied form that involves repositioning of an aromatic residue, Phe114. Although structures of the end-states of the exchange process are available, insight into the mechanism by which the transition takes place cannot be obtained from experiment and the timescales involved are too slow to address using brute force MD. Using spin relaxation NMR methods, we have identified a triple-mutant of T4L that undergoes the same exchange process as T4L L99A but where the minor state lifetime has decreased significantly so that the spontaneous conformational transition to the major state can be studied using all-atom MD simulations. The simulation trajectories were analyzed using Markov state models and the energy landscape so obtained is in good agreement with expectations based on NMR studies. Notably there is no large-scale perturbation of the structure during the transition, multiple intermediates are formed between the two similar exchanging conformations and the free energy barrier between these two well-folded, compact forms is small (6
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