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The role of non-native interactions in the folding of knotted proteins.

Skrbić T, Micheletti C, Faccioli P - PLoS Comput. Biol. (2012)

Bottom Line: In addition, two different sets of pairwise amino acid interactions are considered: one promoting exclusively native interactions, and the other additionally including non-native quasi-chemical and electrostatic interactions.With the additional non-native interactions, knotting propensity remains negligible for the natively-unknotted OTCase while for AOTCase it is much enhanced.Analysis of the trajectories suggests that the different entanglement of the two transcarbamylases follows from the tendency of the C-terminal to point away from (for OTCase) or approach and eventually thread (for AOTCase) other regions of partly-folded protein.

View Article: PubMed Central - PubMed

Affiliation: ECT*- European Centre for Theoretical Studies in Nuclear Physics and Related Areas, Villazzano (Trento), Italy.

ABSTRACT
Stochastic simulations of coarse-grained protein models are used to investigate the propensity to form knots in early stages of protein folding. The study is carried out comparatively for two homologous carbamoyltransferases, a natively-knotted N-acetylornithine carbamoyltransferase (AOTCase) and an unknotted ornithine carbamoyltransferase (OTCase). In addition, two different sets of pairwise amino acid interactions are considered: one promoting exclusively native interactions, and the other additionally including non-native quasi-chemical and electrostatic interactions. With the former model neither protein shows a propensity to form knots. With the additional non-native interactions, knotting propensity remains negligible for the natively-unknotted OTCase while for AOTCase it is much enhanced. Analysis of the trajectories suggests that the different entanglement of the two transcarbamylases follows from the tendency of the C-terminal to point away from (for OTCase) or approach and eventually thread (for AOTCase) other regions of partly-folded protein. The analysis of the OTCase/AOTCase pair clarifies that natively-knotted proteins can spontaneously knot during early folding stages and that non-native sequence-dependent interactions are important for promoting and disfavouring early knotting events.

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Three configurations of the knotted AOTCase in the presence of non-native interactions that illustrate a knotting-unknotting event.Three MC generated coarse-grained configurations (subsequent in MC time): unknotted (left and right) and knotted (middle). The knot results from the threading of a loop (in cyan) by part of the C-terminal -helix (colored in orange).
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pcbi-1002504-g005: Three configurations of the knotted AOTCase in the presence of non-native interactions that illustrate a knotting-unknotting event.Three MC generated coarse-grained configurations (subsequent in MC time): unknotted (left and right) and knotted (middle). The knot results from the threading of a loop (in cyan) by part of the C-terminal -helix (colored in orange).

Mentions: In this respect, it is important to point out that, in the course of the simulations for the AOTCase with non-native interactions, the process of knot formation is not irreversible. As illustrated in Fig. 5, trefoil knots can be formed and untied during each simulation. In particular, fully-developed knots can persists for up to one tenth of the duration of our simulations. Notably, only knots with the correct (i.e. native) chirality are observed.


The role of non-native interactions in the folding of knotted proteins.

Skrbić T, Micheletti C, Faccioli P - PLoS Comput. Biol. (2012)

Three configurations of the knotted AOTCase in the presence of non-native interactions that illustrate a knotting-unknotting event.Three MC generated coarse-grained configurations (subsequent in MC time): unknotted (left and right) and knotted (middle). The knot results from the threading of a loop (in cyan) by part of the C-terminal -helix (colored in orange).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375218&req=5

pcbi-1002504-g005: Three configurations of the knotted AOTCase in the presence of non-native interactions that illustrate a knotting-unknotting event.Three MC generated coarse-grained configurations (subsequent in MC time): unknotted (left and right) and knotted (middle). The knot results from the threading of a loop (in cyan) by part of the C-terminal -helix (colored in orange).
Mentions: In this respect, it is important to point out that, in the course of the simulations for the AOTCase with non-native interactions, the process of knot formation is not irreversible. As illustrated in Fig. 5, trefoil knots can be formed and untied during each simulation. In particular, fully-developed knots can persists for up to one tenth of the duration of our simulations. Notably, only knots with the correct (i.e. native) chirality are observed.

Bottom Line: In addition, two different sets of pairwise amino acid interactions are considered: one promoting exclusively native interactions, and the other additionally including non-native quasi-chemical and electrostatic interactions.With the additional non-native interactions, knotting propensity remains negligible for the natively-unknotted OTCase while for AOTCase it is much enhanced.Analysis of the trajectories suggests that the different entanglement of the two transcarbamylases follows from the tendency of the C-terminal to point away from (for OTCase) or approach and eventually thread (for AOTCase) other regions of partly-folded protein.

View Article: PubMed Central - PubMed

Affiliation: ECT*- European Centre for Theoretical Studies in Nuclear Physics and Related Areas, Villazzano (Trento), Italy.

ABSTRACT
Stochastic simulations of coarse-grained protein models are used to investigate the propensity to form knots in early stages of protein folding. The study is carried out comparatively for two homologous carbamoyltransferases, a natively-knotted N-acetylornithine carbamoyltransferase (AOTCase) and an unknotted ornithine carbamoyltransferase (OTCase). In addition, two different sets of pairwise amino acid interactions are considered: one promoting exclusively native interactions, and the other additionally including non-native quasi-chemical and electrostatic interactions. With the former model neither protein shows a propensity to form knots. With the additional non-native interactions, knotting propensity remains negligible for the natively-unknotted OTCase while for AOTCase it is much enhanced. Analysis of the trajectories suggests that the different entanglement of the two transcarbamylases follows from the tendency of the C-terminal to point away from (for OTCase) or approach and eventually thread (for AOTCase) other regions of partly-folded protein. The analysis of the OTCase/AOTCase pair clarifies that natively-knotted proteins can spontaneously knot during early folding stages and that non-native sequence-dependent interactions are important for promoting and disfavouring early knotting events.

Show MeSH
Related in: MedlinePlus