title: Folding specificity induced by loop stiffness.
abstract: To test the importance of loop stiffness in restricting the heterogeneity of transition state ensemble, we relaxed the distal loop of 10 unstable redesigned hydrophobic core mutants of alpha-spectrin SH3 domain. This was achieved by replacing Asp48 by Gly at the tip of the distal hairpin. Although the change was local in nature, the effect on stabilization was not uniform across the core mutants tested. There is an inverse rough correlation between the stabilization and the increase in buried hydrophobic volume, with respect to the wild type. Interestingly enough, proteins that although unstable are properly folded become molten globule-like after relaxation of the distal loop. These results highlight the importance of stiffness in restricting the conformational heterogeneity of a protein during the folding reaction. An interplay between unspecific hydrophobic interactions and constraint induced by polar interactions, or in this case local stiffness, is essential to achieve a well-ordered folded structure.
authors.affiliation: European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, Heidelberg D-69117, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Spagnolo
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry; D002942:Circular Dichroism; D005916:Globulins / Q000737:chemistry; D005998:Glycine / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D018583:Pliability; D011487:Protein Conformation; D017510:Protein Folding; D013049:Spectrin / Q000737:chemistry / Q000235:genetics*; D013816:Thermodynamics; D018909:src Homology Domains / Q000235:genetics*
chemical_list: D005916:Globulins; D013049:Spectrin; D001224:Aspartic Acid; D005998:Glycine