The role of non-native interactions in the folding of knotted proteins.
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.
ECT*- European Centre for Theoretical Studies in Nuclear Physics and Related Areas, Villazzano (Trento), Italy.
Tatjana
T
Skrbić
Cristian
C
Micheletti
Pietro
P
Faccioli
D019878:Carboxyl and Carbamoyl Transferases / Q000737:chemistry; D019295:Computational Biology; D003198:Computer Simulation; D007700:Kinetics; D008958:Models, Molecular; D009010:Monte Carlo Method; D009954:Ornithine Carbamoyltransferase / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D055672:Static Electricity; D013269:Stochastic Processes
D019878:Carboxyl and Carbamoyl Transferases; C500792:N-acetylornithine transcarbamylase; D009954:Ornithine Carbamoyltransferase