ArticleJournal of chemical theory and computation2015
Biasing Potential Replica Exchange Multisite λ-Dynamics for Efficient Free Energy Calculations.
Article in Journal of chemical theory and computation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed.
- Multiple Molecule λ-Dynamics: Probing Drug Resistance with Concurrent Protein and Ligand Perturbations.The journal of physical chemistry letters · 2025Article
- Predicting Thermodynamic Stability at Protein G Sites with Deleterious Mutations Using λ-Dynamics with Competitive Screening.The journal of physical chemistry letters · 2025Article
- CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed.The journal of physical chemistry. B · 2024Review
- How to Sample Dozens of Substitutions per Site with λ Dynamics.Journal of chemical theory and computation · 2024Article
- Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering.Journal of chemical theory and computation · 2024Article
- Selection pressures on evolution of ribonuclease H explored with rigorous free-energy-based design.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Addressing Intersite Coupling Unlocks Large Combinatorial Chemical Spaces for Alchemical Free Energy Methods.Journal of chemical theory and computation · 2022Article
- Alchemical Free Energy Methods Applied to Complexes of the First Bromodomain of BRD4.Journal of chemical information and modeling · 2022Article
- Best practices for constructing, preparing, and evaluating protein-ligand binding affinity benchmarks [Article v0.1].Living journal of computational molecular science · 2022Article
- Generalizing the Discrete Gibbs Sampler-Based λ-Dynamics Approach for Multisite Sampling of Many Ligands.Journal of chemical theory and computation · 2021Article
- Automated, Accurate, and Scalable Relative Protein-Ligand Binding Free-Energy Calculations Using Lambda Dynamics.Journal of chemical theory and computation · 2020Article
- Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery.Journal of chemical information and modeling · 2020Article
- Improved Alchemical Free Energy Calculations with Optimized Smoothstep Softcore Potentials.Journal of chemical theory and computation · 2020Article
- Repulsive Soft-Core Potentials for Efficient Alchemical Free Energy Calculations.Journal of chemical theory and computation · 2020Article
- Exploring pH Dependent Host/Guest Binding Affinities.The journal of physical chemistry. B · 2020Article
- Sampling Conformational Changes of Bound Ligands Using Nonequilibrium Candidate Monte Carlo and Molecular Dynamics.Journal of chemical theory and computation · 2020Article
- Development of a Robust Indirect Approach for MM → QM Free Energy Calculations That Combines Force-Matched Reference Potential and Bennett's Acceptance Ratio Methods.Journal of chemical theory and computation · 2019Article
- Overcoming Challenging Substituent Perturbations with Multisite λ-Dynamics: A Case Study Targeting β-Secretase 1.The journal of physical chemistry letters · 2019Article
- Approaching protein design with multisite λ dynamics: Accurate and scalable mutational folding free energies in T4 lysozyme.Protein science : a publication of the Protein Society · 2018Article
- Detailed potential of mean force studies on host-guest systems from the SAMPL6 challenge.Journal of computer-aided molecular design · 2018Article
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3 authors.
Funding
Abstract
Traditional free energy calculation methods are well-known for their drawbacks in scalability and speed in converging results particularly for calculations with large perturbations. In the present work, we report on the development of biasing potential replica exchange multisite λ-dynamics (BP-REX MSλD), which is a free energy method that is capable of performing simultaneous alchemical free energy transformations, including perturbations between flexible moieties. BP-REX MSλD and the original MSλD are applied to a series of symmetrical 2,5-benzoquinone derivatives covering a diverse chemical space and range of conformational flexibility. Improved λ-space sampling is observed for the BP-REX MSλD simulations, yielding a 2-5-fold increase in the number of transitions between substituents compared to traditional MSλD. We also demonstrate the efficacy of varying the value of c, the parameter that controls the ruggedness of the landscape mediating the sampling of λ-states, based on the flexibility of the fragment. Finally, we developed a protocol for maximizing the transition frequency between fragments. This protocol reduces the "kinetic barrier" for alchemically transforming fragments by grouping and ordering based on volume. These findings are applied to a challenging test set involving a series of geldanamycin-based inhibitors of heat shock protein 90 (Hsp90). Even though the perturbations span volume changes by as large as 60 Å(3), the values for the free energy change achieve an average unsigned error (AUE) of 1.5 kcal/mol relative to experimental Kd measurements with a reasonable correlation (R = 0.56). Our results suggest that the BP-REX MSλD algorithm is a highly efficient and scalable free energy method, which when utilized will enable routine calculations on the order of hundreds of compounds using only a few simulations.
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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.