ArticleJournal of chemical theory and computation2012
Conformational Transitions and Convergence of Absolute Binding Free Energy Calculations.
Article in Journal of chemical theory and computation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- Computed Protein-Protein Enthalpy Signatures as a Tool for Identifying Conformation Sampling Problems.Journal of chemical information and modeling · 2023Article
- Comparison of Receptor-Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations.Journal of chemical theory and computation · 2023Article
- Free Energy-Based Computational Methods for the Study of Protein-Peptide Binding Equilibria.Methods in molecular biology (Clifton, N.J.) · 2022Article
- New perspectives in cancer drug development: computational advances with an eye to design.RSC medicinal chemistry · 2021Review
- Machine Learning and Enhanced Sampling Simulations for Computing the Potential of Mean Force and Standard Binding Free Energy.Journal of chemical theory and computation · 2021Article
- Estimating the Roles of Protonation and Electronic Polarization in Absolute Binding Affinity Simulations.Journal of chemical theory and computation · 2021Article
- Combining Machine Learning and Enhanced Sampling Techniques for Efficient and Accurate Calculation of Absolute Binding Free Energies.Journal of chemical theory and computation · 2020Article
- Absolute Binding Free Energy Calculations for Highly Flexible Protein MDM2 and Its Inhibitors.International journal of molecular sciences · 2020Article
- Massive-Scale Binding Free Energy Simulations of HIV Integrase Complexes Using Asynchronous Replica Exchange Framework Implemented on the IBM WCG Distributed Network.Journal of chemical information and modeling · 2019Article
- Alchemical Grid Dock (AlGDock) calculations in the D3R Grand Challenge 3 : Binding free energies between flexible ligands and rigid receptors.Journal of computer-aided molecular design · 2019Article
- Specific Residue Interactions Regulate the Binding of Dengue Antigens to Broadly Neutralizing EDE Antibodies.ChemistryOpen · 2018Article
- Improving Prediction Accuracy of Binding Free Energies and Poses of HIV Integrase Complexes Using the Binding Energy Distribution Analysis Method with Flattening Potentials.Journal of chemical information and modeling · 2018Article
- Assessment of a Single Decoupling Alchemical Approach for the Calculation of the Absolute Binding Free Energies of Protein-Peptide Complexes.Frontiers in molecular biosciences · 2018Article
- A combined treatment of hydration and dynamical effects for the modeling of host-guest binding thermodynamics: the SAMPL5 blinded challenge.Journal of computer-aided molecular design · 2017Article
- Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV-1 Reverse Transcriptase.ACS omega · 2016Article
- Simulating Replica Exchange: Markov State Models, Proposal Schemes, and the Infinite Swapping Limit.The journal of physical chemistry. B · 2016Article
- Binding Energy Distribution Analysis Method: Hamiltonian Replica Exchange with Torsional Flattening for Binding Mode Prediction and Binding Free Energy Estimation.Journal of chemical theory and computation · 2016Article
- Locally weighted histogram analysis and stochastic solution for large-scale multi-state free energy estimation.The Journal of chemical physics · 2016Article
- Parameterization of an effective potential for protein-ligand binding from host-guest affinity data.Journal of molecular recognition : JMR · 2016Article
- Asynchronous Replica Exchange Software for Grid and Heterogeneous Computing.Computer physics communications · 2015Article
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Authors and funding
3 authors.
Funding
Abstract
The Binding Energy Distribution Analysis Method (BEDAM) is employed to compute the standard binding free energies of a series of ligands to a FK506 binding protein (FKBP12) with implicit solvation. Binding free energy estimates are in reasonably good agreement with experimental affinities. The conformations of the complexes identified by the simulations are in good agreement with crystallographic data, which was not used to restrain ligand orientations. The BEDAM method is based on λ -hopping Hamiltonian parallel Replica Exchange (HREM) molecular dynamics conformational sampling, the OPLS-AA/AGBNP2 effective potential, and multi-state free energy estimators (MBAR). Achieving converged and accurate results depends on all of these elements of the calculation. Convergence of the binding free energy is tied to the level of convergence of binding energy distributions at critical intermediate states where bound and unbound states are at equilibrium, and where the rate of binding/unbinding conformational transitions is maximal. This finding mirrors similar observations in the context of order/disorder transitions as for example in protein folding. Insights concerning the physical mechanism of ligand binding and unbinding are obtained. Convergence for the largest FK506 ligand is achieved only after imposing strict conformational restraints, which however require accurate prior structural knowledge of the structure of the complex. The analytical AGBNP2 model is found to underestimate the magnitude of the hydrophobic driving force towards binding in these systems characterized by loosely packed protein-ligand binding interfaces. Rescoring of the binding energies using a numerical surface area model corrects this deficiency. This study illustrates the complex interplay between energy models, exploration of conformational space, and free energy estimators needed to obtain robust estimates from binding free energy calculations.
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