ArticlePLoS computational biology2020
Exploring the sequence fitness landscape of a bridge between protein folds.
Article in PLoS computational biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Exploration of the structural and functional diversity in the metamorphic RfaH subfamily.bioRxiv : the preprint server for biology · 2026Article
- Article
- Aromatic-aromatic interactions drive fold switch of GA95 and GB95 with three residue difference.Chemical science · 2025Article
- EvoAI enables extreme compression and reconstruction of the protein sequence space.Nature methods · 2025Article
- Heterogeneous folding landscapes and predetermined breaking points within a protein family.Protein science : a publication of the Protein Society · 2024Article
- High fitness paths can connect proteins with low sequence overlap.bioRxiv : the preprint server for biology · 2024Article
- Article
- Emergent time scales of epistasis in protein evolution.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Simultaneous enhancement of multiple functional properties using evolution-informed protein design.Nature communications · 2024Article
- A systematic analysis of regression models for protein engineering.PLoS computational biology · 2024Article
- EvoAI enables extreme compression and reconstruction of the protein sequence space.Research square · 2024Article
- 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
- Data-driven strategies for the computational design of enzyme thermal stability: trends, perspectives, and prospects.Acta biochimica et biophysica Sinica · 2023Review
- Coevolution-derived native and non-native contacts determine the emergence of a novel fold in a universally conserved family of transcription factors.Protein science : a publication of the Protein Society · 2022Article
- Design principles of protein switches.Current opinion in structural biology · 2022Review
- SYNBIP: synthetic binding proteins for research, diagnosis and therapy.Nucleic acids research · 2022Article
- A sequence-based method for predicting extant fold switchers that undergo α-helix ↔ β-strand transitions.Biopolymers · 2021Article
- A high-throughput predictive method for sequence-similar fold switchers.Biopolymers · 2021Article
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2 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Most foldable protein sequences adopt only a single native fold. Recent protein design studies have, however, created protein sequences which fold into different structures apon changes of environment, or single point mutation, the best characterized example being the switch between the folds of the GA and GB binding domains of streptococcal protein G. To obtain further insight into the design of sequences which can switch folds, we have used a computational model for the fitness landscape of a single fold, built from the observed sequence variation of protein homologues. We have recently shown that such coevolutionary models can be used to design novel foldable sequences. By appropriately combining two of these models to describe the joint fitness landscape of GA and GB, we are able to describe the propensity of a given sequence for each of the two folds. We have successfully tested the combined model against the known series of designed GA/GB hybrids. Using Monte Carlo simulations on this landscape, we are able to identify pathways of mutations connecting the two folds. In the absence of a requirement for domain stability, the most frequent paths go via sequences in which neither domain is stably folded, reminiscent of the propensity for certain intrinsically disordered proteins to fold into different structures according to context. Even if the folded state is required to be stable, we find that there is nonetheless still a wide range of sequences which are close to the transition region and therefore likely fold switches, consistent with recent estimates that fold switching may be more widespread than had been thought.
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