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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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Monte Carlo time evolution of the average knotting probabilities and fraction of native contacts of the “in silico” mutant of the natively-unknotted OTCase.The knotting probabilities observed with the purely native-centric model and with the added non-native interactions are shown in blue and red, respectively. The black curve shows the fraction of native contacts in the presence of non-native interactions.
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pcbi-1002504-g009: Monte Carlo time evolution of the average knotting probabilities and fraction of native contacts of the “in silico” mutant of the natively-unknotted OTCase.The knotting probabilities observed with the purely native-centric model and with the added non-native interactions are shown in blue and red, respectively. The black curve shows the fraction of native contacts in the presence of non-native interactions.

Mentions: To further clarify the role of the C-terminal -helix in the knotting of the partially-folded states of the AOTCase, we have carried out another set of simulations on a mutant protein. The last 25 residues of the OTCase (which are involved in the C-terminal -helix) were substituted with the same number of residues that form the C-terminal -helix in the knotted AOTCase. Apart from such a substitution, all other attributes, namely the length of the chain and the native contact map, were identical to the unknotted protein. The outcome of the simulation is summarized in Fig. 9, from which we can conclude that the mutant protein forms a substantial fraction of knotted configurations in the presence of non-native interactions in its early stage of the folding.


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

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

Monte Carlo time evolution of the average knotting probabilities and fraction of native contacts of the “in silico” mutant of the natively-unknotted OTCase.The knotting probabilities observed with the purely native-centric model and with the added non-native interactions are shown in blue and red, respectively. The black curve shows the fraction of native contacts in the presence of non-native interactions.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1002504-g009: Monte Carlo time evolution of the average knotting probabilities and fraction of native contacts of the “in silico” mutant of the natively-unknotted OTCase.The knotting probabilities observed with the purely native-centric model and with the added non-native interactions are shown in blue and red, respectively. The black curve shows the fraction of native contacts in the presence of non-native interactions.
Mentions: To further clarify the role of the C-terminal -helix in the knotting of the partially-folded states of the AOTCase, we have carried out another set of simulations on a mutant protein. The last 25 residues of the OTCase (which are involved in the C-terminal -helix) were substituted with the same number of residues that form the C-terminal -helix in the knotted AOTCase. Apart from such a substitution, all other attributes, namely the length of the chain and the native contact map, were identical to the unknotted protein. The outcome of the simulation is summarized in Fig. 9, from which we can conclude that the mutant protein forms a substantial fraction of knotted configurations in the presence of non-native interactions in its early stage of the folding.

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