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Denatured proteins and early folding intermediates simulated in a reduced conformational space

100%

Kmiecik S., Kurcinski M., Rutkowska A., Gront D., Kolinski A.

2006

vol. 53

issue 1

131-144

Conformations of globular proteins in the denatured state were studied using a high-resolution lattice model of proteins and Monte Carlo dynamics. The model assumes a united-atom and high-coordination lattice representation of the polypeptide conformational space. The force field of the model mimics the short-range protein-like conformational stiffness, hydrophobic interactions of the side chains and the main-chain hydrogen bonds. Two types of approximations for the short-range interactions were compared: simple statistical potentials and knowledge-based protein-specific potentials derived from the sequence-structure compatibility of short fragments of protein chains. Model proteins in the denatured state are relatively compact, although the majority of the sampled conformations are globally different from the native fold. At the same time short protein fragments are mostly native-like. Thus, the denatured state of the model proteins has several features of the molten globule state observed experimentally. Statistical potentials induce native-like conformational propensities in the denatured state, especially for the fragments located in the core of folded proteins. Knowledge-based protein-specific potentials increase only slightly the level of similarity to the native conformations, in spite of their qualitatively higher specificity in the native structures. For a few cases, where fairly accurate experimental data exist, the simulation results are in semiquantitative agreement with the physical picture revealed by the experiments. This shows that the model studied in this work could be used efficiently in computational studies of protein dynamics in the denatured state, and consequently for studies of protein folding pathways, i.e. not only for the modeling of folded structures, as it was shown in previous studies. The results of the present studies also provide a new insight into the explanation of the Levinthal's paradox.

Protein modeling with reduced representation: statistical potentials and protein folding mechanism

100%

Ekonomiuk D., Kielbasinski M., Andrzej K.

2005

vol. 52

issue 4

741-748

A high resolution reduced model of proteins is used in Monte Carlo dynamics studies of the folding mechanism of a small globular protein, the B1 immunoglobulin-binding domain of streptococcal protein G. It is shown that in order to reproduce the physics of the folding transition, the united atom based model requires a set of knowledge-based potentials mimicking the short-range conformational propensities and protein-like chain stiffness, a model of directional and cooperative hydrogen bonds, and properly designed knowledge-based potentials of the long-range interactions between the side groups. The folding of the model protein is cooperative and very fast. In a single trajectory, a number of folding/unfolding cycles were observed. Typically, the folding process is initiated by assembly of a native-like structure of the C-terminal hairpin. In the next stage the rest of the four-ribbon β-sheet folds. The slowest step of this pathway is the assembly of the central helix on the scaffold of the β-sheet.

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2 Acta Biochimica Polonica

1 2006

1 2005

1 Andrzej K.

1 Ekonomiuk D.

1 Gront D.

1 Kielbasinski M.

1 Kmiecik S.

1 Kolinski A.

1 Kurcinski M.

1 Rutkowska A.

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Denatured proteins and early folding intermediates simulated in a reduced conformational space

Protein modeling with reduced representation: statistical potentials and protein folding mechanism