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Título: | Insights into protein folding mechanisms from large scale analysis of mutational effects. |
Autor: | Naganathan, Athi N. CSIC ORCID; Muñoz, Víctor CSIC ORCID | Palabras clave: | Protein kinetics Protein mutations Protein folding phi-values Protein Stability Protein Structure Free energy relationships Perturbation analysis |
Fecha de publicación: | 11-may-2010 | Editor: | National Academy of Sciences (U.S.) | Citación: | Proceedings of the National Academy of Sciences of the USA, 107(19): 8611-8616 | Resumen: | 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. | Descripción: | This article contains supporting information online at www.pnas.org/cgi/content/full/1000988107/DCSupplemental and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889297/bin/supp_107_19_8611__index.html | Versión del editor: | http://www.pnas.org/content/107/19/8611.long | URI: | http://hdl.handle.net/10261/41701 | DOI: | 10.1073/pnas.1000988107 | ISSN: | 1091-6490 |
Aparece en las colecciones: | (CIB) Artículos |
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