ArticleBiophysical journal2019
Mechanisms for Benzene Dissociation through the Excited State of T4 Lysozyme L99A Mutant.
Article in Biophysical journal, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Residence time in drug discovery: current insights and future perspectives.Pharmacological reports : PR · 2025Review
- Ligand Gaussian Accelerated Molecular Dynamics 3 (LiGaMD3): Improved Calculations of Binding Thermodynamics and Kinetics of Both Small Molecules and Flexible Peptides.Journal of chemical theory and computation · 2024Article
- Ligand Gaussian accelerated Molecular Dynamics 3 (LiGaMD3): Improved Calculations of Binding Thermodynamics and Kinetics of Both Small Molecules and Flexible Peptides.bioRxiv : the preprint server for biology · 2024Article
- Local Xenon-Protein Interaction Produces Global Conformational Change and Allosteric Inhibition in Lysozyme.Biochemistry · 2023Article
- Ligand Gaussian Accelerated Molecular Dynamics 2 (LiGaMD2): Improved Calculations of Ligand Binding Thermodynamics and Kinetics with Closed Protein Pocket.Journal of chemical theory and computation · 2023Article
- Automated Path Searching Reveals the Mechanism of Hydrolysis Enhancement by T4 Lysozyme Mutants.International journal of molecular sciences · 2022Article
- Energy penalties enhance flexible receptor docking in a model cavity.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Ligand unbinding mechanisms and kinetics for T4 lysozyme mutants from τRAMD simulations.Current research in structural biology · 2021Article
- Flexible Fitting of Small Molecules into Electron Microscopy Maps Using Molecular Dynamics Simulations with Neural Network Potentials.Journal of chemical information and modeling · 2020Article
- De Novo Prediction of Binders and Nonbinders for T4 Lysozyme by gREST Simulations.Journal of chemical information and modeling · 2019Article
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7 authors.
Funding
Abstract
The atomic-level mechanisms that coordinate ligand release from protein pockets are only known for a handful of proteins. Here, we report results from accelerated molecular dynamics simulations for benzene dissociation from the buried cavity of the T4 lysozyme Leu99Ala mutant (L99A). In these simulations, benzene is released through a previously characterized, sparsely populated room-temperature excited state of the mutant, explaining the coincidence for experimentally measured benzene off rate and apo protein slow-timescale NMR relaxation rates between ground and excited states. The path observed for benzene egress is a multistep ligand migration from the buried cavity to ultimate release through an opening between the F/G-, H-, and I-helices and requires a number of cooperative multiresidue and secondary-structure rearrangements within the C-terminal domain of L99A. These rearrangements are identical to those observed along the ground state to excited state transitions characterized by molecular dynamic simulations run on the Anton supercomputer. Analyses of the molecular properties of the residues lining the egress path suggest that protein surface electrostatic potential may play a role in the release mechanism. Simulations of wild-type T4 lysozyme also reveal that benzene-egress-associated dynamics in the L99A mutant are potentially exaggerations of the substrate-processivity-related dynamics of the wild type.
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