ArticleProceedings of the National Academy of Sciences of the United States of America2010
Insights into protein folding mechanisms from large scale analysis of mutational effects.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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56 citing papers in PubMed, 105 citations in OpenAlex.
- Article
- Phi-Value and NMR Structural Analysis of a Coupled Native-State Prolyl Isomerization and Conformational Protein Folding Process.Biomolecules · 2025Article
- Targeting the protein folding transition state by mutation: Large scale (un)folding rate accelerations without altering native stability.Protein science : a publication of the Protein Society · 2024Article
- Single-Molecule Imaging of Integral Membrane Protein Dynamics and Function.Annual review of biophysics · 2024Review
- PON-Fold: Prediction of Substitutions Affecting Protein Folding Rate.International journal of molecular sciences · 2023Article
- Protein folding rate evolution upon mutations.Biophysical reviews · 2023Review
- VariBench, new variation benchmark categories and data sets.Frontiers in bioinformatics · 2023Article
- Assessment of potassium ion channel during electric signalling in biofilm formation ofHeliyon · 2023Article
- Topological bio-scaling analysis as a universal measure of protein folding.Royal Society open science · 2022Article
- Predicting and Simulating Mutational Effects on Protein Folding Kinetics.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Engineered Metal-Binding Sites to Probe Protein Folding Transition States: Psi Analysis.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Mutational Analysis of Protein Folding Transition States: Phi Values.Methods in molecular biology (Clifton, N.J.) · 2022Article
- The Next Frontier for Designing Switchable Proteins: Rational Enhancement of Kinetics.The journal of physical chemistry. B · 2021Article
- Converging experimental and computational views of the knotting mechanism of a small knotted protein.Biophysical journal · 2021Article
- Cooperative hydrophobic core interactions in the β-trefoil architecture.Protein science : a publication of the Protein Society · 2021Article
- Templated folding of intrinsically disordered proteins.The Journal of biological chemistry · 2020Review
- Effects of Topology and Sequence in Protein Folding Linked via Conformational Fluctuations.Biophysical journal · 2020Article
- Substrate binding in the processive cellulase Cel7A: Transition state of complexation and roles of conserved tryptophan residues.The Journal of biological chemistry · 2020Article
- Ultrafast folding kinetics of WW domains reveal how the amino acid sequence determines the speed limit to protein folding.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Modulation of allosteric coupling by mutations: from protein dynamics and packing to altered native ensembles and function.Current opinion in structural biology · 2019Review
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein folding mechanisms are probed experimentally using single-point mutant perturbations. The relative effects on the folding (phi-values) and unfolding (1 - phi) rates are used to infer the detailed structure of the transition-state ensemble (TSE). Here we analyze kinetic data on > 800 mutations carried out for 24 proteins with simple kinetic behavior. We find two surprising results: (i) all mutant effects are described by the equation: DeltaDeltaG(double dagger)(unfold)=0.76DeltaDeltaG(eq) +/- 1.8kJ/mol. Therefore all data are consistent with a single phi-value (0.24) with accuracy comparable to experimental precision, suggesting that the structural information in conventional phi-values is low. (ii) phi-values change with stability, increasing in mean value and spread from native to unfolding conditions, and thus cannot be interpreted without proper normalization. We eliminate stability effects calculating the phi-values at the mutant denaturation midpoints; i.e., conditions of zero stability (phi(0)). We then show that the intrinsic variability is phi(0) = 0.36 +/- 0.11, being somewhat larger for beta-sheet-rich proteins than for alpha-helical proteins. Importantly, we discover that phi(0)-values are proportional to how many of the residues surrounding the mutated site are local in sequence. High phi(0)-values correspond to protein surface sites, which have few nonlocal neighbors, whereas core residues with many tertiary interactions produce the lowest phi(0)-values. These results suggest a general mechanism in which the TSE at zero stability is a broad conformational ensemble stabilized by local interactions and without specific tertiary interactions, reconciling phi-values with many other empirical observations.
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