ArticleFrontiers in chemistry2018
Computational Study of Protein-Ligand Unbinding for Enzyme Engineering.
Article in Frontiers in chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- The Discovery of Small ERK5 Inhibitors via Structure-Based Virtual Screening, Biological Evaluation and MD Simulations.Molecules (Basel, Switzerland) · 2025Article
- Reinforcing Tunnel Network Exploration in Proteins Using Gaussian Accelerated Molecular Dynamics.Journal of chemical information and modeling · 2024Article
- Exploring Product Release from Yeast Cytosine Deaminase with Metadynamics.The journal of physical chemistry. B · 2024Article
- In silico investigation of cholesterol-lowering drugs to find potential inhibitors of dehydrosqualene synthase in3 Biotech · 2024Article
- Diphenyl Diselenide and SARS-CoV-2:Journal of chemical information and modeling · 2023Article
- The Discovery of Small Allosteric and Active Site Inhibitors of the SARS-CoV-2 Main Protease via Structure-Based Virtual Screening and Biological Evaluation.Molecules (Basel, Switzerland) · 2022Article
- Article
- Determination of Multidirectional Pathways for Ligand Release from the Receptor: A New Approach Based on Differential Evolution.Journal of chemical theory and computation · 2022Article
- Recent advances in user-friendly computational tools to engineer protein function.Briefings in bioinformatics · 2021Review
- Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 main protease complexes reveal the role of lateral pocket in enhancing the ligand affinity.Scientific reports · 2021Article
- Thermodynamics and Kinetics of Drug-Target Binding by Molecular Simulation.Chemical reviews · 2020Review
- Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering.International journal of molecular sciences · 2020Review
- Determining the unbinding events and conserved motions associated with the pyrazinamide release due to resistance mutations ofComputational and structural biotechnology journal · 2020Article
- Caver Web 1.0: identification of tunnels and channels in proteins and analysis of ligand transport.Nucleic acids research · 2019Article
- Machine Learning Analysis of τRAMD Trajectories to Decipher Molecular Determinants of Drug-Target Residence Times.Frontiers in molecular biosciences · 2019Article
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Authors and funding
3 authors.
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No grant is acknowledged in the PubMed record.
Abstract
The computational prediction of unbinding rate constants is presently an emerging topic in drug design. However, the importance of predicting kinetic rates is not restricted to pharmaceutical applications. Many biotechnologically relevant enzymes have their efficiency limited by the binding of the substrates or the release of products. While aiming at improving the ability of our model enzyme haloalkane dehalogenase DhaA to degrade the persistent anthropogenic pollutant 1,2,3-trichloropropane (TCP), the DhaA31 mutant was discovered. This variant had a 32-fold improvement of the catalytic rate toward TCP, but the catalysis became rate-limited by the release of the 2,3-dichloropropan-1-ol (DCP) product from its buried active site. Here we present a computational study to estimate the unbinding rates of the products from DhaA and DhaA31. The metadynamics and adaptive sampling methods were used to predict the relative order of kinetic rates in the different systems, while the absolute values depended significantly on the conditions used (method, force field, and water model). Free energy calculations provided the energetic landscape of the unbinding process. A detailed analysis of the structural and energetic bottlenecks allowed the identification of the residues playing a key role during the release of DCP from DhaA31 via the main access tunnel. Some of these hot-spots could also be identified by the fast CaverDock tool for predicting the transport of ligands through tunnels. Targeting those hot-spots by mutagenesis should improve the unbinding rates of the DCP product and the overall catalytic efficiency with TCP.
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