Pathway diversity and concertedness in protein folding: an ab-initio approach

Journal of Biomolecular Structure & Dynamics
Andrés Colubri, Ariel Fernández

Abstract

Making use of an ab-initio folding simulator, we generate in vitro pathways leading to the native fold in moderate size single- domain proteins. The assessment of pathway diversity is not biased by any a priori information on the native fold. We focus on two study cases, hyperthermophile variant of protein G domain (1gb4) and ubiquitin (1ubi), with the same topology but different context dependence in their native folds. We demonstrate that a quenching of structural fluctuations is achieved once the proteins find a stationary plateau maximizing the number of highly protected hydrogen bonds. This enables us to identify the folding nucleus and show that folding does not become expeditious until a concerted event takes place generating a topology able to prevent water attack on a maximal number of hydrogen bonds. This result is consistent with the standard nucleation mechanism postulated for two-state folders. Pathway diversity is correlated with the extent of conflict between local structural propensity and large-scale context, rather than with contact order: In highly context-dependent proteins, the success of folding cannot rely on a single fortuitous event in which local propensity is overruled by large-scale effects. We predi...Continue Reading

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Citations

Nov 7, 2002·Journal of Molecular Biology·Ariel FernándezAndrés Colubri
Feb 11, 2004·Journal of Biomolecular Structure & Dynamics·Andrés Colubri
Sep 24, 2004·Biophysical Chemistry·Neelan J Marianayagam, Sophie E Jackson
Sep 20, 2006·Journal of Molecular Biology·Andrés ColubriKarl F Freed

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