title: Morphogenesis of a protein: folding pathways and the energy landscape.
abstract: Current knowledge on the reaction whereby a protein acquires its native three-dimensional structure was obtained by and large through characterization of the folding mechanism of simple systems. Given the multiplicity of amino acid sequences and unique folds, it is not so easy, however, to draw general rules by comparing folding pathways of different proteins. In fact, quantitative comparison may be jeopardized not only because of the vast repertoire of sequences but also in view of a multiplicity of structures of the native and denatured states. We have tackled the problem of the relationships between the sequence information and the folding pathway of a protein, using a combination of kinetics, protein engineering and computational methods, applied to relatively simple systems. Our strategy has been to investigate the folding mechanism determinants using two complementary approaches, i.e. (i) the study of members of the same family characterized by a common fold, but substantial differences in amino acid sequence, or (ii) heteromorphic pairs characterized by largely identical sequences but with different folds. We discuss some recent data on protein-folding mechanisms by presenting experiments on different members of the PDZ domain family and their circularly permuted variants. Characterization of the energetics and structures of intermediates and TSs (transition states), obtained by Φ-value analysis and restrained MD (molecular dynamics) simulations, provides a glimpse of the malleability of the dynamic states and of the role of the topology of the native states and of the denatured states in dictating folding and misfolding pathways.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti and Istituto di Biologia e Patologia Molecolari del CNR, Dipartimento di Scienze Biochimiche A. Rossi Fanelli, Università di Roma La Sapienza, Rome, Italy. maurizio.brunori@uniroma1.it
authors.forename: Maurizio
authors.initials: M
authors.lastname: Brunori
authors.forename: Stefano
authors.initials: S
authors.lastname: Gianni
authors.forename: Rajanish
authors.initials: R
authors.lastname: Giri
authors.forename: Angela
authors.initials: A
authors.lastname: Morrone
authors.forename: Carlo
authors.initials: C
authors.lastname: Travaglini-Allocatelli
mesh_terms: D000818:Animals; D006801:Humans; D007700:Kinetics; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D011506:Proteins