ArticleProtein science : a publication of the Protein Society2016
Computational scheme for pH-dependent binding free energy calculation with explicit solvent.
Article in Protein science : a publication of the Protein Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed.
- Computing the pH-Dependent Thermodynamics of the Allostery between Dimerization and Palmitate Binding in β-Lactoglobulin.The journal of physical chemistry. B · 2025Article
- CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed.The journal of physical chemistry. B · 2024Review
- Constant pH molecular dynamics simulations: Current status and recent applications.Current opinion in structural biology · 2022Review
- An overview of the SAMPL8 host-guest binding challenge.Journal of computer-aided molecular design · 2022Article
- Article
- Obtaining QM/MM binding free energies in the SAMPL8 drugs of abuse challenge: indirect approaches.Journal of computer-aided molecular design · 2022Article
- 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
- Exploring pH Dependent Host/Guest Binding Affinities.The journal of physical chemistry. B · 2020Article
- Molecular Dynamics Simulations of Membrane Permeability.Chemical reviews · 2019Review
- An explicit-solvent hybrid QM and MM approach for predicting pKa of small molecules in SAMPL6 challenge.Journal of computer-aided molecular design · 2018Article
- Overview of the SAMPL6 host-guest binding affinity prediction challenge.Journal of computer-aided molecular design · 2018Article
- A fast and accurate computational method for the linear-combination-based isotropic periodic sum.Scientific reports · 2018Article
- Critical test of isotropic periodic sum techniques with group-based cut-off schemes.Scientific reports · 2018Article
- Development of constant-pH simulation methods in implicit solvent and applications in biomolecular systems.Biophysical reviews · 2017Review
- Origin of pKThe journal of physical chemistry. B · 2017Article
- Absolute binding free energy calculations of CBClip host-guest systems in the SAMPL5 blind challenge.Journal of computer-aided molecular design · 2017Article
- Calculating distribution coefficients based on multi-scale free energy simulations: an evaluation of MM and QM/MM explicit solvent simulations of water-cyclohexane transfer in the SAMPL5 challenge.Journal of computer-aided molecular design · 2016Article
- Isotropic periodic sum for multipole interactions and a vector relation for calculation of the Cartesian multipole tensor.The Journal of chemical physics · 2016Article
- Continuum Electrostatics Approaches to Calculating pKas and Ems in Proteins.Methods in enzymology · 2016Review
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3 authors.
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Abstract
We present a computational scheme to compute the pH-dependence of binding free energy with explicit solvent. Despite the importance of pH, the effect of pH has been generally neglected in binding free energy calculations because of a lack of accurate methods to model it. To address this limitation, we use a constant-pH methodology to obtain a true ensemble of multiple protonation states of a titratable system at a given pH and analyze the ensemble using the Bennett acceptance ratio (BAR) method. The constant pH method is based on the combination of enveloping distribution sampling (EDS) with the Hamiltonian replica exchange method (HREM), which yields an accurate semi-grand canonical ensemble of a titratable system. By considering the free energy change of constraining multiple protonation states to a single state or releasing a single protonation state to multiple states, the pH dependent binding free energy profile can be obtained. We perform benchmark simulations of a host-guest system: cucurbit[7]uril (CB[7]) and benzimidazole (BZ). BZ experiences a large pKa shift upon complex formation. The pH-dependent binding free energy profiles of the benchmark system are obtained with three different long-range interaction calculation schemes: a cutoff, the particle mesh Ewald (PME), and the isotropic periodic sum (IPS) method. Our scheme captures the pH-dependent behavior of binding free energy successfully. Absolute binding free energy values obtained with the PME and IPS methods are consistent, while cutoff method results are off by 2 kcal mol(-1) . We also discuss the characteristics of three long-range interaction calculation methods for constant-pH simulations.
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