ArticleJournal of chemical theory and computation2022
Addressing Intersite Coupling Unlocks Large Combinatorial Chemical Spaces for Alchemical Free Energy Methods.
Article in Journal of chemical theory and computation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed.
- Accelerated Combinatorial Drug Design for Human Immunodeficiency Virus Resistance through Seeded Multisite λ-Dynamics.Journal of chemical theory and computation · 2026Article
- Approaches for regulating enzyme activities: Recent advances in experiment and computation.Current opinion in structural biology · 2025Review
- Multiple Molecule λ-Dynamics: Probing Drug Resistance with Concurrent Protein and Ligand Perturbations.The journal of physical chemistry letters · 2025Article
- Multisite λ-Dynamics for Protein-DNA Binding Affinity Prediction.Journal of chemical theory and computation · 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
- A λ-Dynamics Investigation of InsulinJournal of chemical information and modeling · 2024Article
- A λ-dynamics investigation of insulinbioRxiv : the preprint server for biology · 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
- Fast free energy estimates from λ-dynamics with bias-updated Gibbs sampling.Nature communications · 2023Article
- QSAR via multisite λ-dynamics in the orphaned TSSK1B kinase.Protein science : a publication of the Protein Society · 2023Article
- Evolutionary divergence in the conformational landscapes of tyrosine vs serine/threonine kinases.eLife · 2022Article
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3 authors.
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Abstract
Alchemical free energy methods are playing a growing role in molecular design, both for computer-aided drug design of small molecules and for computational protein design. Multisite λ dynamics (MSλD) is a uniquely scalable alchemical free energy method that enables more efficient exploration of combinatorial alchemical spaces encountered in molecular design, but simulations have typically been limited to a few hundred ligands or sequences. Here, we focus on coupling between sites to enable scaling to larger alchemical spaces. We first discuss updates to the biasing potentials that facilitate MSλD sampling to include coupling terms and show that this can provide more thorough sampling of alchemical states. We then harness coupling between sites by developing a new free energy estimator based on the Potts models underlying direct coupling analysis, a method for predicting contacts from sequence coevolution, and find it yields more accurate free energies than previous estimators. The sampling requirements of the Potts model estimator scale with the square of the number of sites, a substantial improvement over the exponential scaling of the standard estimator. This opens up exploration of much larger alchemical spaces with MSλD for molecular design.
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