Atomic resolution mechanism of ligand binding to a solvent inaccessible cavity in T4 lysozyme

PLoS Computational Biology
Jagannath MondalPramodh Vallurupalli

Abstract

Ligand binding sites in proteins are often localized to deeply buried cavities, inaccessible to bulk solvent. Yet, in many cases binding of cognate ligands occurs rapidly. An intriguing system is presented by the L99A cavity mutant of T4 Lysozyme (T4L L99A) that rapidly binds benzene (~106 M-1s-1). Although the protein has long served as a model system for protein thermodynamics and crystal structures of both free and benzene-bound T4L L99A are available, the kinetic pathways by which benzene reaches its solvent-inaccessible binding cavity remain elusive. The current work, using extensive molecular dynamics simulation, achieves this by capturing the complete process of spontaneous recognition of benzene by T4L L99A at atomistic resolution. A series of multi-microsecond unbiased molecular dynamics simulation trajectories unequivocally reveal how benzene, starting in bulk solvent, diffuses to the protein and spontaneously reaches the solvent inaccessible cavity of T4L L99A. The simulated and high-resolution X-ray derived bound structures are in excellent agreement. A robust four-state Markov model, developed using cumulative 60 μs trajectories, identifies and quantifies multiple ligand binding pathways with low activation barrier...Continue Reading

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Citations

Jan 16, 2019·PLoS Computational Biology·Dheeraj DubeSurajit Sengupta
Apr 29, 2020·The Journal of Biological Chemistry·Deborah E A LockhartDaan M F van Aalten
Jul 28, 2020·Nature Communications·Paulo C T SouzaSiewert J Marrink
Feb 24, 2020·The Journal of Chemical Physics·Navjeet AhalawatJagannath Mondal
Oct 24, 2020·The Journal of Chemical Physics·Dhiman RayIoan Andricioaei
Jun 11, 2020·The Journal of Physical Chemistry Letters·Bhupendra R Dandekar, Jagannath Mondal
Apr 16, 2021·Frontiers in Molecular Biosciences·Paulo C T SouzaLuca Monticelli
Jul 9, 2021·Current Research in Structural Biology·Ariane Nunes-AlvesRebecca C Wade
Dec 15, 2018·Biochemistry·João Marcelo Lamim RibeiroPratyush Tiwary
Aug 8, 2019·Journal of Chemical Information and Modeling·Ai NiitsuYuji Sugita
Jan 1, 2021·The Journal of Physical Chemistry Letters·Navjeet Ahalawat, Jagannath Mondal
Dec 12, 2018·Journal of Chemical Theory and Computation·João Marcelo Lamim Ribeiro, Pratyush Tiwary
Sep 4, 2021·Proceedings of the National Academy of Sciences of the United States of America·Anna S KamenikBrian K Shoichet
Sep 19, 2020·Biophysical Journal·Dhiman Ray, Ioan Andricioaei
Nov 4, 2021·Expert Opinion on Drug Discovery·Qianqian ZhangHuanxiang Liu

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Methods Mentioned

BETA
X-ray
NMR
protein folding

Software Mentioned

PyEMMA
Metadynamics
TALOS
CHARMM
NMRPipe
AMBER
SPARKY
tICA
Gromacs

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