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

Ventura S, Vega MC, Lacroix E, Angrand I, Spagnolo L, Serrano L
Nat Struct Biol 9 485-93 (2002)
Related entries: 1e6h, 1h8k, 1shg

Cited: 67 times
EuropePMC logo 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 x mol(-1)). Several of these Ile-->Val mutants have negative phi(-U) values, indicating that some noncanonical phi(-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.

Articles - 1e6g mentioned but not cited (1)

  1. High-resolution structure of an alpha-spectrin SH3-domain mutant with a redesigned hydrophobic core. Cámara-Artigas A, Andújar-Sánchez M, Ortiz-Salmerón E, Cuadri C, Cobos ES, Martin-Garcia JM. Acta Crystallogr Sect F Struct Biol Cryst Commun 66 1023-1027 (2010)


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Related citations provided by authors (1)

  1. Crystal structure of a Src-homology 3 (SH3) domain.. Musacchio A, Noble M, Pauptit R, Wierenga R, Saraste M Nature 359 851-5 (1992)

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