ArticleJournal of computational chemistry2021
A strategy for proline and glycine mutations to proteins with alchemical free energy calculations.
Article in Journal of computational chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 27 citations in OpenAlex.
- 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
- 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
- High throughput mutational scanning of a protein via alchemistry on a high-performance computing resource.bioRxiv : the preprint server for biology · 2024Article
- Replica Exchange of Expanded Ensembles: A Generalized Ensemble Approach with Enhanced Flexibility and Parallelizability.Journal of chemical theory and computation · 2024Article
- How to Sample Dozens of Substitutions per Site with λ Dynamics.Journal of chemical theory and computation · 2024Article
- A Membrane-Assisted Mechanism for the Release of Ceramide from the CERT START Domain.The journal of physical chemistry. B · 2024Article
- Potts Hamiltonian Models and Molecular Dynamics Free Energy Simulations for Predicting the Impact of Mutations on Protein Kinase Stability.The journal of physical chemistry. B · 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
- Accurate and efficient protein sequence design through learning concise local environment of residues.Bioinformatics (Oxford, England) · 2023Article
- Addressing Intersite Coupling Unlocks Large Combinatorial Chemical Spaces for Alchemical Free Energy Methods.Journal of chemical theory and computation · 2022Article
- BLaDE: A Basic Lambda Dynamics Engine for GPU-Accelerated Molecular Dynamics Free Energy Calculations.Journal of chemical theory and computation · 2021Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Computation of the thermodynamic consequences of protein mutations holds great promise in protein biophysics and design. Alchemical free energy methods can give improved estimates of mutational free energies, and are already widely used in calculations of relative and absolute binding free energies in small molecule design problems. In principle, alchemical methods can address any amino acid mutation with an appropriate alchemical pathway, but identifying a strategy that produces such a path for proline and glycine mutations is an ongoing challenge. Most current strategies perturb only side chain atoms, while proline and glycine mutations also alter the backbone parameters and backbone ring topology. Some strategies also perturb backbone parameters and enable glycine mutations. This work presents a strategy that enables both proline and glycine mutations and comprises two key elements: a dual backbone with restraints and scaling of bonded terms, facilitating backbone parameter changes, and a soft bond in the proline ring, enabling ring topology changes in proline mutations. These elements also have utility for core hopping and macrocycle studies in computer-aided drug design. This new strategy shows slight improvements over an alternative side chain perturbation strategy for a set T4 lysozyme mutations lacking proline and glycine, and yields good agreement with experiment for a set of T4 lysozyme proline and glycine mutations not previously studied. To our knowledge this is the first report comparing alchemical predictions of proline mutations with experiment. With this strategy in hand, alchemical methods now have access to the full palette of amino acid mutations.
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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.