ArticleJournal of chemical theory and computation2021
Variational Method for Networkwide Analysis of Relative Ligand Binding Free Energies with Loop Closure and Experimental Constraints.
Article in Journal of chemical theory and computation, 2021. 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, 35 citations in OpenAlex.
- Origins of Reactivity in SAM-Utilizing Ribozyme SAMURI-Catalyzed RNA Alkylation.Journal of the American Chemical Society · 2026Article
- Efficient Binding Affinity Estimation for Fragment-Based Compounds Using a Separated Topologies Approach.Journal of chemical information and modeling · 2026Article
- A Relative Binding Free Energy Framework for Structurally Dissimilar Molecules.Journal of chemical information and modeling · 2026Article
- Recent Developments in Amber Biomolecular Simulations.Journal of chemical information and modeling · 2025Article
- Comparative Analysis of Quantum-Mechanical and Standard Single-Structure Protein-Ligand Scoring Functions with MD-Based Free Energy Calculations.Journal of chemical information and modeling · 2025Article
- FE-ToolKit: A Versatile Software Suite for Analysis of High-Dimensional Free Energy Surfaces and Alchemical Free Energy Networks.Journal of chemical information and modeling · 2025Article
- Adaptive Lambda Scheduling: A Method for Computational Efficiency in Free Energy Perturbation Simulations.Journal of chemical information and modeling · 2025Article
- The Role of General Acid Catalysis in the Mechanism of an Alkyl Transferase Ribozyme.ACS catalysis · 2024Article
- Improvements in Precision of Relative Binding Free Energy Calculations Afforded by the Alchemical Enhanced Sampling (ACES) Approach.Journal of chemical information and modeling · 2024Article
- Adsorption of Flavonoids in a Transcriptional Regulator TtgR: Relative Binding Free Energies and Intermolecular Interactions.The journal of physical chemistry. B · 2024Article
- Alchemical Enhanced Sampling with Optimized Phase Space Overlap.Journal of chemical theory and computation · 2024Article
- Alchemical Free Energy Workflows for the Computation of Protein-Ligand Binding Affinities.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Modern Alchemical Free Energy Methods for Drug Discovery Explained.ACS physical chemistry Au · 2023Review
- AmberTools.Journal of chemical information and modeling · 2023Article
- ACES: Optimized Alchemically Enhanced Sampling.Journal of chemical theory and computation · 2023Article
- AMBER Free Energy Tools: A New Framework for the Design of Optimized Alchemical Transformation Pathways.Journal of chemical theory and computation · 2023Article
- AMBER Drug Discovery Boost Tools: Automated Workflow for Production Free-Energy Simulation Setup and Analysis (ProFESSA).Journal of chemical information and modeling · 2022Article
- Accurate Binding Free Energy Method from End-State MD Simulations.Journal of chemical information and modeling · 2022Article
- Relative Binding Free Energy between Chemically Distant Compounds Using a Bidirectional Nonequilibrium Approach.Journal of chemical theory and computation · 2022Article
- Free Energy-Based Computational Methods for the Study of Protein-Peptide Binding Equilibria.Methods in molecular biology (Clifton, N.J.) · 2022Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
We describe an efficient method for the simultaneous solution of all free energies within a relative binding free-energy (RBFE) network with cycle closure and experimental/reference constraint conditions using Bennett Acceptance Ratio (BAR) and Multistate BAR (MBAR) analysis. Rather than solving the BAR or MBAR equations for each transformation independently, the simultaneous solution of all transformations are obtained by performing a constrained minimization of a global objective function. The nonlinear optimization of the objective function is subjected to affine linear constraints that couple the free energies between the network edges. The constraints are used to enforce the closure of thermodynamic cycles within the RBFE network, and to enforce an additional set of linear constraint conditions demonstrated here to be subsets of (1 or 2) experimental values. We describe details of the practical implementation of the network BAR/MBAR procedure, including use of generalized coordinates in the minimization of the free-energy objective function, propagation of bootstrap errors from those coordinates, and performance and memory optimization. In some cases it is found that use of restraints in the optimization is more practical than use of generalized coordinates for enforcing constraint conditions. The fast BARnet and MBARnet methods are used to analyze the RBFEs of six prototypical protein-ligand systems, and it is shown that enforcement of cycle closure conditions reduces the error in the predictions only modestly, and further reduction in errors can be achieved when one or two experimental RBFEs are included in the optimization procedure. These methods have been implemented into FE-ToolKit, a new free-energy analysis toolkit. The BARnet/MBARnet framework presented here opens the door to new, more efficient and robust free-energy analysis with enhanced predictive capability for drug discovery applications.
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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.