Effects of knot type in the folding of topologically complex lattice proteins

Abstract

The folding properties of a protein whose native structure contains a 52 knot are investigated by means of extensive Monte Carlo simulations of a simple lattice model and compared with those of a 31 knot. A 52 knot embedded in the native structure enhances the kinetic stability of the carrier lattice protein in a way that is clearly more pronounced than in the case of the 31 knot. However, this happens at the expense of a severe loss in folding efficiency, an observation that is consistent with the relative abundance of 31 and 52 knots in the Protein Data Bank. The folding mechanism of the 52 knot shares with that of the 31 knot the occurrence of a threading movement of the chain terminus that lays closer to the knotted core. However, co-concomitant knotting and folding in the 52 knot occurs with negligible probability, in sharp contrast to what is observed for the 31 knot. The study of several single point mutations highlights the importance in the folding of knotted proteins of the so-called structural mutations (i.e., energetic perturbations of native interactions between residues that are critical for knotting but not for folding). On the other hand, the present study predicts that mutations that perturb the folding transition state may significantly enhance the kinetic stability of knotted proteins provided they involve residues located within the knotted core.

Knotting and unknotting of a protein in single molecule experiments

“…Our results can also be compared with values from computational studies where it is facile to create an unknotted variant of a knotted protein with the same secondary structural elements packed against each other in the same manner but with a different connectivity, essentially "rewiring" the polypeptide chain. Coarse-grained lattice-based approaches have been used to estimate the effect knots on the folding and unfolding rates of a model system (56). A 5 2 knot had an effect on both the folding rate (k ).…”

Knotted proteins: Tie etiquette in structural biology

“…The number of theoretical articles in the literature addressing this problem is scarce. To the best of our knowledge Virnau and co-workers were the first to explore the folding of protein DehI, embedding a deep 6 1 knot (18), and Soler et al (98) were the first to study the folding of a lattice model system with a shallow 5 2 knot (98). More recently, Sulkowska and coworkers, provided the first off-lattice results for protein Ubiquitin C-terminal Hydrolase L1 (UCH-L1) (PDB ID: 3irt) embedding a shallow 5 2 knot in its native structure (99).…”

Molekulare Knoten

“…[161] Obwohl Proteinknoten nicht zwangsweise eine bestimmte Aufgabe erfüllen, ist es bemerkenswert, dass Ubiquitin-Hydrolase besonders entfaltungsresistent sein muss.D ieses Enzym ist in Form eines 5 2 -Knotens gefaltet, und es konnte gezeigt werden, dass eine komplexe Verknotung Proteinen kinetische Stabilitätv erleiht. [162,163] Da die meisten verknoteten Proteine Enzyme sind und sich der Knoten normalerweise in der katalytischen Domäne befindet, kçnnten Knoten einen wichtigen Einfluss auf die enzymatische Aktivität haben. [164,165] Es wurde gezeigt, dass die Anwesenheit eines Cysteinknotens im Kern einem Protein eine außergewçhnli-che Stabilitätverleiht.…”