ArticleJournal of the American Chemical Society2015
Spatial analysis and quantification of the thermodynamic driving forces in protein-ligand binding: binding site variability.
Article in Journal of the American Chemical Society, 2015. 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, 27 citations in OpenAlex.
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- Implicit Solvent with Explicit Ions Generalized Born Model in Molecular Dynamics: Application to DNA.Journal of chemical theory and computation · 2024Article
- Inclusion of Water Multipoles into the Implicit Solvation Framework Leads to Accuracy Gains.The journal of physical chemistry. B · 2024Article
- Improving the Accuracy of Physics-Based Hydration-Free Energy Predictions by Machine Learning the Remaining Error Relative to the Experiment.Journal of chemical theory and computation · 2024Article
- A Closed-Form, Analytical Approximation for Apparent Surface Charge and Electric Field of Molecules.ACS omega · 2022Article
- Energy-entropy method using multiscale cell correlation to calculate binding free energies in the SAMPL8 host-guest challenge.Journal of computer-aided molecular design · 2021Article
- Thermodynamic Decomposition of Solvation Free Energies with Particle Mesh Ewald and Long-Range Lennard-Jones Interactions in Grid Inhomogeneous Solvation Theory.Journal of chemical theory and computation · 2021Article
- Free Energies and Entropies of Binding Sites Identified by MixMD Cosolvent Simulations.Journal of chemical information and modeling · 2019Article
- Predicting Displaceable Water Sites Using Mixed-Solvent Molecular Dynamics.Journal of chemical information and modeling · 2018Article
- Solvation Structure and Thermodynamic Mapping (SSTMap): An Open-Source, Flexible Package for the Analysis of Water in Molecular Dynamics Trajectories.Journal of chemical theory and computation · 2018Article
- Hot-spot identification on a broad class of proteins and RNA suggest unifying principles of molecular recognition.PloS one · 2017Article
- Driving Structure-Based Drug Discovery through Cosolvent Molecular Dynamics.Journal of medicinal chemistry · 2016Review
- AutoDock-GIST: Incorporating Thermodynamics of Active-Site Water into Scoring Function for Accurate Protein-Ligand Docking.Molecules (Basel, Switzerland) · 2016Article
- Enthalpic and Entropic Contributions to Hydrophobicity.Journal of chemical theory and computation · 2016Article
- Quantitative Correlation of Conformational Binding Enthalpy with Substrate Specificity of Serine Proteases.The journal of physical chemistry. B · 2016Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The thermodynamic driving forces behind small molecule-protein binding are still not well-understood, including the variability of those forces associated with different types of ligands in different binding pockets. To better understand these phenomena we calculate spatially resolved thermodynamic contributions of the different molecular degrees of freedom for the binding of propane and methanol to multiple pockets on the proteins Factor Xa and p38 MAP kinase. Binding thermodynamics are computed using a statistical thermodynamics based end-point method applied on a canonical ensemble comprising the protein-ligand complexes and the corresponding free states in an explicit solvent environment. Energetic and entropic contributions of water and ligand degrees of freedom computed from the configurational ensemble provide an unprecedented level of detail into the mechanisms of binding. Direct protein-ligand interaction energies play a significant role in both nonpolar and polar binding, which is comparable to water reorganization energy. Loss of interactions with water upon binding strongly compensates these contributions leading to relatively small binding enthalpies. For both solutes, the entropy of water reorganization is found to favor binding in agreement with the classical view of the "hydrophobic effect". Depending on the specifics of the binding pocket, both energy-entropy compensation and reinforcement mechanisms are observed. It is notable to have the ability to visualize the spatial distribution of the thermodynamic contributions to binding at atomic resolution showing significant differences in the thermodynamic contributions of water to the binding of propane versus methanol.
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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.