ArticleeLife2016
Mapping transiently formed and sparsely populated conformations on a complex energy landscape.
Article in eLife, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Structural dynamics in chromatin unraveling by pioneer transcription factors.Biophysical reviews · 2024Review
- Uncovering the Kinetic Characteristics and Degradation Preference of PROTAC Systems with Advanced Theoretical Analyses.JACS Au · 2023Article
- Systematic conformation-to-phenotype mapping via limited deep sequencing of proteins.Molecular cell · 2023Article
- Insights into membrane association of the SMP domain of extended synaptotagmin.Nature communications · 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
- Article
- Automated Path Searching Reveals the Mechanism of Hydrolysis Enhancement by T4 Lysozyme Mutants.International journal of molecular sciences · 2022Article
- Transient exposure of a buried phosphorylation site in an autoinhibited protein.Biophysical journal · 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
- Investigating Conformational Dynamics and Allostery in the p53 DNA-Binding Domain Using Molecular Simulations.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Ligand unbinding mechanisms and kinetics for T4 lysozyme mutants from τRAMD simulations.Current research in structural biology · 2021Article
- DEER-PREdict: Software for efficient calculation of spin-labeling EPR and NMR data from conformational ensembles.PLoS computational biology · 2021Article
- Wepy: A Flexible Software Framework for Simulating Rare Events with Weighted Ensemble Resampling.ACS omega · 2020Article
- Protein Dynamics Enables Phosphorylation of Buried Residues in Cdk2/Cyclin-A-Bound p27.Biophysical journal · 2020Article
- Targeting a critical step in fungal hexosamine biosynthesis.The Journal of biological chemistry · 2020Article
- Local frustration determines loop opening during the catalytic cycle of an oxidoreductase.eLife · 2020Article
- Dynamic design: manipulation of millisecond timescale motions on the energy landscape of cyclophilin A.Chemical science · 2020Article
- De Novo Prediction of Binders and Nonbinders for T4 Lysozyme by gREST Simulations.Journal of chemical information and modeling · 2019Article
- Mechanisms for Benzene Dissociation through the Excited State of T4 Lysozyme L99A Mutant.Biophysical journal · 2019Article
- Dynamic disulfide exchange in a crystallin protein in the human eye lens promotes cataract-associated aggregation.The Journal of biological chemistry · 2018Article
Corrections and comments
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Authors and funding
3 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.