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 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 disfavouring early knotting events.