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Folding specificity induced by loop stiffness

European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, Heidelberg D-69117, Germany

Reprint requests to: Luis Serrano, EMBL, Meyerhofstrasse 1, Heidelberg D-69117, Germany; e-mail: serrano{at}embl-heidelberg.de; fax: +49–6221–387306.

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 -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.

Keywords: Design; proteins; hydrophobic core; kinetics

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