Conformational strain in the hydrophobic core and its implications for protein folding and design

Ventura, S., Vega, M. C., Lacroix, E., Angrand, I., Spagnolo, L. and Serrano, L. (2002) Conformational strain in the hydrophobic core and its implications for protein folding and design. Nature Structural Biology, 9(6), pp. 485-493. (doi: 10.1038/nsb799) (PMID:12006985)

Abstract

We have designed de novo 13 divergent spectrin SH3 core sequences to determine their folding properties. Kinetic analysis of the variants with stability similar to that of the wild type protein shows accelerated unfolding and refolding rates compatible with a preferential stabilization of the transition state. This is most likely caused by conformational strain in the native state, as deletion of a methyl group (Ile→Val) leads to deceleration in unfolding and increased stability (up to 2 kcal mol−1). Several of these Ile→Val mutants have negative φ‡−U values, indicating that some noncanonical φ‡−U values might result from conformational strain. Thus, producing a stable protein does not necessarily mean that the design process has been entirely successful. Strained interactions could have been introduced, and a reduction in the buried volume could result in a large increase in stability and a reduction in unfolding rates.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Spagnolo, Professor Laura
• Authors: Ventura, S., Vega, M. C., Lacroix, E., Angrand, I., Spagnolo, L., and Serrano, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Nature Structural Biology
• Publisher: Nature Publishing Group
• ISSN: 1072-8368