ArticlePLoS computational biology2016
Theoretical Insights into the Biophysics of Protein Bi-stability and Evolutionary Switches.
Article in PLoS computational biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Signatures of protein fold switching in the unfolded state.Biophysical journal · 2026Article
- Article
- How the Extent of Protein Folding and Oligomerization Modulate Condensate Formation and Properties.The journal of physical chemistry letters · 2025Article
- Article
- Seesaw protein: Design of a protein that adopts interconvertible alternative functional conformations and its dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Aromatic-aromatic interactions drive fold switch of GA95 and GB95 with three residue difference.Chemical science · 2025Article
- Ancestral Reconstruction and the Evolution of Protein Energy Landscapes.Annual review of biophysics · 2024Review
- SSDraw: Software for generating comparative protein secondary structure diagrams.Protein science : a publication of the Protein Society · 2023Article
- SSDraw: software for generating comparative protein secondary structure diagrams.bioRxiv : the preprint server for biology · 2023Article
- Identification of a covert evolutionary pathway between two protein folds.Nature communications · 2023Article
- A high-throughput predictive method for sequence-similar fold switchers.Biopolymers · 2021Article
- Two β-Lactamase Variants with Reduced Clavulanic Acid Inhibition Display Different Millisecond Dynamics.Antimicrobial agents and chemotherapy · 2021Article
- Exploring the sequence fitness landscape of a bridge between protein folds.PLoS computational biology · 2020Article
- Effects of Topology and Sequence in Protein Folding Linked via Conformational Fluctuations.Biophysical journal · 2020Article
- Protein ensembles link genotype to phenotype.PLoS computational biology · 2019Review
- Conformational dynamics and enzyme evolution.Journal of the Royal Society, Interface · 2018Review
- Large enhancement of response times of a protein conformational switch by computational design.Nature communications · 2018Article
- Effects of pH and Salt Concentration on Stability of a Protein G Variant Using Coarse-Grained Models.Biophysical journal · 2018Article
- Molecular recognition and packing frustration in a helical protein.PLoS computational biology · 2017Article
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Authors and funding
3 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Deciphering the effects of nonsynonymous mutations on protein structure is central to many areas of biomedical research and is of fundamental importance to the study of molecular evolution. Much of the investigation of protein evolution has focused on mutations that leave a protein's folded structure essentially unchanged. However, to evolve novel folds of proteins, mutations that lead to large conformational modifications have to be involved. Unraveling the basic biophysics of such mutations is a challenge to theory, especially when only one or two amino acid substitutions cause a large-scale conformational switch. Among the few such mutational switches identified experimentally, the one between the GA all-α and GB α+β folds is extensively characterized; but all-atom simulations using fully transferrable potentials have not been able to account for this striking switching behavior. Here we introduce an explicit-chain model that combines structure-based native biases for multiple alternative structures with a general physical atomic force field, and apply this construct to twelve mutants spanning the sequence variation between GA and GB. In agreement with experiment, we observe conformational switching from GA to GB upon a single L45Y substitution in the GA98 mutant. In line with the latent evolutionary potential concept, our model shows a gradual sequence-dependent change in fold preference in the mutants before this switch. Our analysis also indicates that a sharp GA/GB switch may arise from the orientation dependence of aromatic π-interactions. These findings provide physical insights toward rationalizing, predicting and designing evolutionary conformational switches.
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