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.
Highlights
A much debated problem in the thermodynamics and kinetics of protein folding [1,2] is the process of knot formation in proteins [3,4,5,6,7,8]
The results indicate that the sequence-dependent non-native interactions – promoted by the quasi-chemical potential – increase dramatically the incidence of knots in the partially folded state of the a natively-knotted Nacetylornithine carbamoyltransferase (AOTCase) compared to the ornithine carbamoyltransferase (OTCase)
Summary and conclusions A simplified coarse-grained protein model was used for a comparative study of early folding stages of two evolutionarily related transcarbamylase proteins: an AOTCase (PDB id 2g68) and an OTCase (PDB id 1pvv)
Summary
A much debated problem in the thermodynamics and kinetics of protein folding [1,2] is the process of knot formation in proteins [3,4,5,6,7,8]. The free energy landscape of proteins, unlike that of homopolymers or random heteropolymers, is sufficiently smooth to ensure that the same knot in the same protein location is observed in folded structures [20,21,22,23,24,25]. These distinctive features are arguably the consequence of concomitant effects, including the propensity of polypeptides to form secondary structure elements, which enhance their local order compared to a typical collapsed polymer chain [9], as well as functionally-oriented evolutionary mechanisms [26,27,28]. A relatively late stage of knot formation q*40% was
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