ArticleProtein science : a publication of the Protein Society2018
Approaching protein design with multisite λ dynamics: Accurate and scalable mutational folding free energies in T4 lysozyme.
Article in Protein science : a publication of the Protein Society, 2018. 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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30 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
- EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery.bioRxiv : the preprint server for biology · 2026Article
- Accurate in silico predictions of modified RNA interactions to a prototypical RNA-binding protein with λ-dynamics.RNA (New York, N.Y.) · 2025Article
- Simultaneous Construction of Free Energy Surfaces via Multisite λ Dynamics and Umbrella Sampling.Journal of chemical theory and computation · 2025Article
- Core Flipping in Lead Optimization: Rank Ordering Using λ-Dynamics.Journal of chemical information and modeling · 2025Article
- 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
- In silico λ-dynamics predicts protein binding specificities to modified RNAs.Nucleic acids research · 2025Article
- Superimposing Ligands with a Ligand Overlay as an Alternate Topology Model for λ-Dynamics-Based Calculations.The journal of physical chemistry. B · 2024Article
- 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 Membrane-Assisted Mechanism for the Release of Ceramide from the CERT START Domain.The journal of physical chemistry. B · 2024Article
- A λ-dynamics investigation of insulinbioRxiv : the preprint server for biology · 2024Article
- Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering.Journal of chemical theory and computation · 2024Article
- In silico λ-dynamics predicts protein binding specificities to modified RNAs.bioRxiv : 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
- Redesigning methionyl-tRNA synthetase for β-methionine activity with adaptive landscape flattening and experiments.Protein science : a publication of the Protein Society · 2023Article
- QSAR via multisite λ-dynamics in the orphaned TSSK1B kinase.Protein science : a publication of the Protein Society · 2023Article
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3 authors.
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Abstract
The estimation of changes in free energy upon mutation is central to the problem of protein design. Modern protein design methods have had remarkable success over a wide range of design targets, but are reaching their limits in ligand binding and enzyme design due to insufficient accuracy in mutational free energies. Alchemical free energy calculations have the potential to supplement modern design methods through more accurate molecular dynamics based prediction of free energy changes, but suffer from high computational cost. Multisite λ dynamics (MSλD) is a particularly efficient and scalable free energy method with potential to explore combinatorially large sequence spaces inaccessible with other free energy methods. This work aims to quantify the accuracy of MSλD and demonstrate its scalability. We apply MSλD to the classic problem of calculating folding free energies in T4 lysozyme, a system with a wealth of experimental measurements. Single site mutants considering 32 mutations show remarkable agreement with experiment with a Pearson correlation of 0.914 and mean unsigned error of 1.19 kcal/mol. Multisite mutants in systems with up to five concurrent mutations spanning 240 different sequences show comparable agreement with experiment. These results demonstrate the promise of MSλD in exploring large sequence spaces for protein design.
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