†Vinicius G. Contessoto and Debora T. Lima contributed equally to this work.
Analyzing the effect of homogeneous frustration in protein folding
Article first published online: 22 JUL 2013
Copyright © 2013 Wiley Periodicals, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 81, Issue 10, pages 1727–1737, October 2013
How to Cite
Contessoto, V. G., Lima, D. T., Oliveira, R. J., Bruni, A. T., Chahine, J. and Leite, V. B. P. (2013), Analyzing the effect of homogeneous frustration in protein folding. Proteins, 81: 1727–1737. doi: 10.1002/prot.24309
- Issue published online: 11 SEP 2013
- Article first published online: 22 JUL 2013
- Accepted manuscript online: 23 APR 2013 02:35AM EST
- Manuscript Accepted: 18 MAR 2013
- Manuscript Revised: 13 MAR 2013
- Manuscript Received: 26 SEP 2012
- Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
- structure-based model;
- multivariate analysis;
- molecular dynamics;
- C-alpha model
The energy landscape theory has been an invaluable theoretical framework in the understanding of biological processes such as protein folding, oligomerization, and functional transitions. According to the theory, the energy landscape of protein folding is funneled toward the native state, a conformational state that is consistent with the principle of minimal frustration. It has been accepted that real proteins are selected through natural evolution, satisfying the minimum frustration criterion. However, there is evidence that a low degree of frustration accelerates folding. We examined the interplay between topological and energetic protein frustration. We employed a Cα structure-based model for simulations with a controlled nonspecific energetic frustration added to the potential energy function. Thermodynamics and kinetics of a group of 19 proteins are completely characterized as a function of increasing level of energetic frustration. We observed two well-separated groups of proteins: one group where a little frustration enhances folding rates to an optimal value and another where any energetic frustration slows down folding. Protein energetic frustration regimes and their mechanisms are explained by the role of non-native contact interactions in different folding scenarios. These findings strongly correlate with the protein free-energy folding barrier and the absolute contact order parameters. These computational results are corroborated by principal component analysis and partial least square techniques. One simple theoretical model is proposed as a useful tool for experimentalists to predict the limits of improvements in real proteins.Proteins 2013; 81:1727–1737. © 2013 Wiley Periodicals, Inc.