  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 show 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 disfavoring early knotting events.
