ArticlePhysical chemistry chemical physics : PCCP2018
Comparing alchemical and physical pathway methods for computing the absolute binding free energy of charged ligands.
Article in Physical chemistry chemical physics : PCCP, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Toward Reconciling the Standard Binding Free Energy of Lenacapavir to HIV-1 Capsid with Experiment: Thermodynamic Effects of Solvent Buffer and Ligand Reorganization.The journal of physical chemistry. B · 2026Article
- Automated On-the-Fly Optimization of Resource Allocation for Efficient Free Energy Simulations.Journal of chemical information and modeling · 2025Article
- Computational Evaluation of Peptide-Protein Binding Affinities: Application of Potential of Mean Force Calculations to SH2 Domains.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Evolutionary divergence in the conformational landscapes of tyrosine vs serine/threonine kinases.eLife · 2022Article
- Correction Schemes for Absolute Binding Free Energies Involving Lipid Bilayers.Journal of chemical theory and computation · 2022Article
- Accurate determination of protein:ligand standard binding free energies from molecular dynamics simulations.Nature protocols · 2022Review
- Developing end-point methods for absolute binding free energy calculation using the Boltzmann-quasiharmonic model.Physical chemistry chemical physics : PCCP · 2022Article
- Structure-based virtual screening workflow to identify antivirals targeting HIV-1 capsid.Journal of computer-aided molecular design · 2022Article
- A highly accurate metadynamics-based Dissociation Free Energy method to calculate protein-protein and protein-ligand binding potencies.Scientific reports · 2022Article
- The Molecular Mechanism of Human Voltage-Dependent Anion Channel 1 Blockade by the Metallofullerenol Gd@CBiomolecules · 2022Article
- First Principles Calculation of Protein-Protein Dimer Affinities of ALS-Associated SOD1 Mutants.Frontiers in molecular biosciences · 2022Article
- Application of the alchemical transfer and potential of mean force methods to the SAMPL8 host-guest blinded challenge.Journal of computer-aided molecular design · 2022Article
- Dummy Atoms in Alchemical Free Energy Calculations.Journal of chemical theory and computation · 2021Article
- AMOEBA binding free energies for the SAMPL7 TrimerTrip host-guest challenge.Journal of computer-aided molecular design · 2021Article
- Recent Developments in Free Energy Calculations for Drug Discovery.Frontiers in molecular biosciences · 2021Review
- Charge-Changing Perturbations and Path Sampling via Classical Molecular Dynamic Simulations of Simple Guest-Host Systems.Journal of chemical theory and computation · 2020Article
- Prediction of ligand binding mode among multiple cross-docking poses by molecular dynamics simulations.Journal of computer-aided molecular design · 2020Article
- Exploring the Free-Energy Landscape and Thermodynamics of Protein-Protein Association.Biophysical journal · 2020Article
- The SAMPL6 SAMPLing challenge: assessing the reliability and efficiency of binding free energy calculations.Journal of computer-aided molecular design · 2020Article
- Combining Alchemical Transformation with a Physical Pathway to Accelerate Absolute Binding Free Energy Calculations of Charged Ligands to Enclosed Binding Sites.Journal of chemical theory and computation · 2020Article
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6 authors.
Funding
Abstract
Accurately predicting absolute binding free energies of protein-ligand complexes is important as a fundamental problem in both computational biophysics and pharmaceutical discovery. Calculating binding free energies for charged ligands is generally considered to be challenging because of the strong electrostatic interactions between the ligand and its environment in aqueous solution. In this work, we compare the performance of the potential of mean force (PMF) method and the double decoupling method (DDM) for computing absolute binding free energies for charged ligands. We first clarify an unresolved issue concerning the explicit use of the binding site volume to define the complexed state in DDM together with the use of harmonic restraints. We also provide an alternative derivation for the formula for absolute binding free energy using the PMF approach. We use these formulas to compute the binding free energy of charged ligands at an allosteric site of HIV-1 integrase, which has emerged in recent years as a promising target for developing antiviral therapy. As compared with the experimental results, the absolute binding free energies obtained by using the PMF approach show unsigned errors of 1.5-3.4 kcal mol-1, which are somewhat better than the results from DDM (unsigned errors of 1.6-4.3 kcal mol-1) using the same amount of CPU time. According to the DDM decomposition of the binding free energy, the ligand binding appears to be dominated by nonpolar interactions despite the presence of very large and favorable intermolecular ligand-receptor electrostatic interactions, which are almost completely cancelled out by the equally large free energy cost of desolvation of the charged moiety of the ligands in solution. We discuss the relative strengths of computing absolute binding free energies using the alchemical and physical pathway methods.
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