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http://hdl.handle.net/2445/147783
Title: | Exploring the early stages of chemical unfolding of proteins at the proteome scale |
Author: | Candotti, Michela Pérez, Alberto Ferrer Costa, Carles Rueda Borrego, Manuel Meyer, Tim Gelpí Buchaca, Josep Lluís Orozco López, Modesto |
Keywords: | Desnaturalització de proteïnes Urea Protein denaturation Urea |
Issue Date: | 12-Dec-2013 |
Publisher: | Public Library of Science (PLoS) |
Abstract: | After decades of using urea as denaturant, the kinetic role of this molecule in the unfolding process is still undefined: does urea actively induce protein unfolding or passively stabilize the unfolded state? By analyzing a set of 30 proteins (representative of all native folds) through extensive molecular dynamics simulations in denaturant (using a range of force-fields), we derived robust rules for urea unfolding that are valid at the proteome level. Irrespective of the protein fold, presence or absence of disulphide bridges, and secondary structure composition, urea concentrates in the first solvation shell of quasi-native proteins, but with a density lower than that of the fully unfolded state. The presence of urea does not alter the spontaneous vibration pattern of proteins. In fact, it reduces the magnitude of such vibrations, leading to a counterintuitive slow down of the atomic-motions that opposes unfolding. Urea stickiness and slow diffusion is, however, crucial for unfolding. Long residence urea molecules placed around the hydrophobic core are crucial to stabilize partially open structures generated by thermal fluctuations. Our simulations indicate that although urea does not favor the formation of partially open microstates, it is not a mere spectator of unfolding that simply displaces to the right of the folded←→unfolded equilibrium. On the contrary, urea actively favors unfolding: it selects and stabilizes partially unfolded microstates, slowly driving the protein conformational ensemble far from the native one and also from the conformations sampled during thermal unfolding. |
Note: | Reproducció del document publicat a: https://doi.org/10.1371/journal.pcbi.1003393 |
It is part of: | PLoS Computational Biology, 2013, vol. 9, num. 12, p. e1003393 |
URI: | http://hdl.handle.net/2445/147783 |
Related resource: | https://doi.org/10.1371/journal.pcbi.1003393 |
ISSN: | 1553-734X |
Appears in Collections: | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona)) |
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