title: Frustration Sculpts the Early Stages of Protein Folding.
abstract: The funneled energy landscape theory implies that protein structures are minimally frustrated. Yet, because of the divergent demands between folding and function, regions of frustrated patterns are present at the active site of proteins. To understand the effects of such local frustration in dictating the energy landscape of proteins, here we compare the folding mechanisms of the two alternative spliced forms of a PDZ domain (PDZ2 and PDZ2as) that share a nearly identical sequence and structure, while displaying different frustration patterns. The analysis, based on the kinetic characterization of a large number of site-directed mutants, reveals that although the late stages for folding are very robust and biased by native topology, the early stages are more malleable and dominated by local frustration. The results are briefly discussed in the context of the energy-landscape theory.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti and Istituto di Biologia e Patologia Molecolari del CNR, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" Sapienza, University of Rome, 00185 Rome (Italy).
authors.forename: Eva
authors.initials: E
authors.lastname: Di Silvio
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti and Istituto di Biologia e Patologia Molecolari del CNR, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" Sapienza, University of Rome, 00185 Rome (Italy).
authors.forename: Maurizio
authors.initials: M
authors.lastname: Brunori
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti and Istituto di Biologia e Patologia Molecolari del CNR, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" Sapienza, University of Rome, 00185 Rome (Italy). stefano.gianni@uniroma1.it.|Department of Chemistry, University of Cambridge, Cambridge CB2 1EW (UK). stefano.gianni@uniroma1.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gianni
mesh_terms: D017398:Alternative Splicing; D016297:Mutagenesis, Site-Directed; D017510:Protein Folding; D011506:Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D011506:Proteins
keywords: frustrated proteins; kinetics; mutagenesis; protein folding