ArticleThe journal of physical chemistry. A2021
Extension of the Variational Free Energy Profile and Multistate Bennett Acceptance Ratio Methods for High-Dimensional Potential of Mean Force Profile Analysis.
Article in The journal of physical chemistry. A, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Origins of Reactivity in SAM-Utilizing Ribozyme SAMURI-Catalyzed RNA Alkylation.Journal of the American Chemical Society · 2026Article
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- 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
- Transferability of MACE Graph Neural Network for Range Corrected Δ-Machine Learning Potential QM/MM Applications.The journal of physical chemistry. B · 2025Article
- Molecular Principles of Proton-Coupled Quinone Reduction in the Membrane-Bound Superoxide Oxidase.Journal of the American Chemical Society · 2025Article
- Electronic and Nuclear Quantum Effects on Proton Transfer Reactions of Guanine-Thymine (G-T) Mispairs Using Combined Quantum Mechanical/Molecular Mechanical and Machine Learning Potentials.Molecules (Basel, Switzerland) · 2024Article
- Alchemical Enhanced Sampling with Optimized Phase Space Overlap.Journal of chemical theory and computation · 2024Article
- Surface-Accelerated String Method for Locating Minimum Free Energy Paths.Journal of chemical theory and computation · 2024Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Modern Alchemical Free Energy Methods for Drug Discovery Explained.ACS physical chemistry Au · 2023Review
- AmberTools.Journal of chemical information and modeling · 2023Article
- Catalytic mechanism and pH dependence of a methyltransferase ribozyme (MTR1) from computational enzymology.Nucleic acids research · 2023Article
- Estimation of frequency factors for the calculation of kinetic isotope effects from classical and path integral free energy simulations.The Journal of chemical physics · 2023Article
- AMBER Drug Discovery Boost Tools: Automated Workflow for Production Free-Energy Simulation Setup and Analysis (ProFESSA).Journal of chemical information and modeling · 2022Article
- Multireference Generalization of the Weighted Thermodynamic Perturbation Method.The journal of physical chemistry. A · 2022Article
- Article
- Combined QM/MM, Machine Learning Path Integral Approach to Compute Free Energy Profiles and Kinetic Isotope Effects in RNA Cleavage Reactions.Journal of chemical theory and computation · 2022Article
- Development of Range-Corrected Deep Learning Potentials for Fast, Accurate Quantum Mechanical/Molecular Mechanical Simulations of Chemical Reactions in Solution.Journal of chemical theory and computation · 2021Article
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Authors and funding
3 authors.
Funding
Abstract
We redevelop the variational free energy profile (vFEP) method using a cardinal B-spline basis to extend the method for analyzing free energy surfaces (FESs) involving three or more reaction coordinates. We also implemented software for evaluating high-dimensional profiles based on the multistate Bennett acceptance ratio (MBAR) method which constructs an unbiased probability density from global reweighting of the observed samples. The MBAR method takes advantage of a fast algorithm for solving the unbinned weighted histogram (UWHAM)/MBAR equations which replaces the solution of simultaneous equations with a nonlinear optimization of a convex function. We make use of cardinal B-splines and multiquadric radial basis functions to obtain smooth, differentiable MBAR profiles in arbitrary high dimensions. The cardinal B-spline vFEP and MBAR methods are compared using three example systems that examine 1D, 2D, and 3D profiles. Both methods are found to be useful and produce nearly indistinguishable results. The vFEP method is found to be 150 times faster than MBAR when applied to periodic 2D profiles, but the MBAR method is 4.5 times faster than vFEP when evaluating unbounded 3D profiles. In agreement with previous comparisons, we find the vFEP method produces superior FESs when the overlap between umbrella window simulations decreases. Finally, the associative reaction mechanism of hammerhead ribozyme is characterized using 3D, 4D, and 6D profiles, and the higher-dimensional profiles are found to have smaller reaction barriers by as much as 1.5 kcal/mol. The methods presented here have been implemented into the FE-ToolKit software package along with new methods for network-wide free energy analysis in drug discovery.
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Registered trials
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