Atomistic picture of conformational exchange in a T4 lysozyme cavity mutant: an experiment-guided molecular dynamics study

Chemical Science
Pramodh VallurupalliLewis E Kay

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 b...Continue Reading

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Citations

Jan 16, 2019·PLoS Computational Biology·Dheeraj DubeSurajit Sengupta
Feb 9, 2018·Nature·Isaac J KimseyHashim M Al-Hashimi
May 30, 2019·The Journal of Membrane Biology·Rajeswari AppaduraiAnand Srivastava
Oct 1, 2020·Journal of Biomolecular NMR·Jan H OverbeckRemco Sprangers
Apr 6, 2018·Chemical Science·Yong WangKresten Lindorff-Larsen
May 19, 2018·PLoS Computational Biology·Jagannath MondalPramodh Vallurupalli
Oct 3, 2018·Journal of Biomolecular NMR·Anusha B GopalanPramodh Vallurupalli
Jul 23, 2020·Journal of Biomolecular NMR·Ved Prakash Tiwari, Pramodh Vallurupalli
Dec 14, 2019·Current Opinion in Structural Biology·T Reid Alderson, Lewis E Kay
Jan 3, 2018·Journal of Chemical Theory and Computation·Po-Chia ChenJanosch Hennig
Aug 8, 2019·Journal of Chemical Information and Modeling·Ai NiitsuYuji Sugita
Dec 14, 2016·Journal of the American Chemical Society·Simon Olsson, Frank Noé
May 14, 2019·The Journal of Physical Chemistry Letters·Pramodh VallurupalliShamasree Ghosh
Sep 15, 2018·Journal of Chemical Theory and Computation·Rafael NunesPaulo J Costa
Sep 4, 2021·Proceedings of the National Academy of Sciences of the United States of America·Anna S KamenikBrian K Shoichet

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Methods Mentioned

BETA
Nuclear Magnetic Resonance
NMR
X-ray
protein folding

Software Mentioned

CHARMM27
Chimera
MSMBuilder
GROMACS
VMD
EMMA

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