ArticleThe journal of physical chemistry. B2015
Protocols utilizing constant pH molecular dynamics to compute pH-dependent binding free energies.
Article in The journal of physical chemistry. B, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Article
- Ω-Loop mutations control dynamics of the active site by modulating the hydrogen-bonding network in PDC-3 β-lactamase.bioRxiv : the preprint server for biology · 2025Article
- Computing the pH-Dependent Thermodynamics of the Allostery between Dimerization and Palmitate Binding in β-Lactoglobulin.The journal of physical chemistry. B · 2025Article
- Enhanced and Efficient Predictions of Dynamic Ionization through Constant-pH Adiabatic Free Energy Dynamics.Journal of chemical theory and computation · 2024Article
- Constant pH molecular dynamics simulations: Current status and recent applications.Current opinion in structural biology · 2022Review
- Article
- Approach to Study pH-Dependent Protein Association Using Constant-pH Molecular Dynamics: Application to the Dimerization of β-Lactoglobulin.Journal of chemical theory and computation · 2022Article
- Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery.Journal of chemical information and modeling · 2020Article
- Proton Relay Network in the Bacterial P450s: CYP101A1 and CYP101D1.Biochemistry · 2020Article
- Exploring pH Dependent Host/Guest Binding Affinities.The journal of physical chemistry. B · 2020Article
- Host-guest complexes of imazalil with cucurbit[8]uril and β-cyclodextrin and their effect on plant pathogenic fungi.Scientific reports · 2018Article
- Origin of pKThe journal of physical chemistry. B · 2017Article
- Computational scheme for pH-dependent binding free energy calculation with explicit solvent.Protein science : a publication of the Protein Society · 2016Article
- Computation of pH-dependent binding free energies.Biopolymers · 2016Review
- Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria.PLoS computational biology · 2015Article
- Interpretation of pH-activity profiles for acid-base catalysis from molecular simulations.Biochemistry · 2015Article
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4 authors.
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Abstract
In protein-ligand binding, the electrostatic environments of the two binding partners may vary significantly in bound and unbound states, which may lead to protonation changes upon binding. In cases where ligand binding results in a net uptake or release of protons, the free energy of binding is pH-dependent. Nevertheless, conventional free energy calculations and molecular docking protocols typically do not rigorously account for changes in protonation that may occur upon ligand binding. To address these shortcomings, we present a simple methodology based on Wyman's binding polynomial formalism to account for the pH dependence of binding free energies and demonstrate its use on cucurbit[7]uril (CB[7]) host-guest systems. Using constant pH molecular dynamics and a reference binding free energy that is taken either from experiment or from thermodynamic integration computations, the pH-dependent binding free energy is determined. This computational protocol accurately captures the large pKa shifts observed experimentally upon CB[7]:guest association and reproduces experimental binding free energies at different levels of pH. We show that incorrect assignment of fixed protonation states in free energy computations can give errors of >2 kcal/mol in these host-guest systems. Use of the methods presented here avoids such errors, thus suggesting their utility in computing proton-linked binding free energies for protein-ligand complexes.
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