Non-native interactions, effective contact order, and protein folding: a mutational investigation with the energetically frustrated hydrophobic model.
Proteins
; 49(2): 167-80, 2002 Nov 01.
Article
em En
| MEDLINE
| ID: mdl-12210998
By Monte Carlo simulations, we explored the effect of single mutations on the thermodynamics and kinetics of the folding of a two-dimensional, energetically frustrated, hydrophobic protein model. Phi-Value analysis, corroborated by simulations beginning from given sets of judiciously chosen initial contacts, suggests that the transition state of the model consists of a limited region of the native structure, that is, a folding nucleus. It seems that the most important contacts in the transition state (large and positive Phi) are not the ones with the highest contact order, because in this case the entropic cost of their formation would be too high, but exactly the ones that decrease the entropic cost of difficult contacts, reducing their effective contact order. Mutations of internal monomers involved in high-order contacts were actually the ones resulting in the fastest kinetics (and Phi < 0), indicating they tend to make low order, non-native contacts of low entropic cost that stabilize the unfolded state with respect to the transition state. Folding acceleration by other non-native interactions was also observed and a simple general mechanism is proposed according to which non-native contacts can act indirectly over the folding nucleus, "chelating" out potentially harmful contacts. The polymer graph of our model, which facilitates the visualization of effective contact orders, successfully suggests the relative kinetic importance of different contacts and is reasonably consistent with analogous graphs for the well characterized family of SH3 domains.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Conformação Proteica
/
Proteínas
/
Método de Monte Carlo
/
Modelos Biológicos
Tipo de estudo:
Health_economic_evaluation
Idioma:
En
Revista:
Proteins
Assunto da revista:
BIOQUIMICA
Ano de publicação:
2002
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Estados Unidos