Abstract
For several decades, the presence of knots in naturally-occurring proteins was largely ruled out a priori for its supposed incompatibility with the efficiency and robustness of folding processes. For this very same reason, the later discovery of several unrelated families of knotted proteins motivated researchers to look into the physico-chemical mechanisms governing the concerted sequence of folding steps leading to the consistent formation of the same knot type in the same protein location. Besides experiments, computational studies are providing considerable insight into these mechanisms. Here, we revisit a number of such recent investigations within a common conceptual and methodological framework. By considering studies employing protein models with different structural resolution (coarse-grained or atomistic) and various force fields (from pure native-centric to realistic atomistic ones), we focus on the role of native and non-native interactions. For various unrelated instances of knotted proteins, non-native interactions are shown to be very important for favoring the emergence of conformations primed for successful self-knotting events.
Highlights
Since the 1994 first survey of non-trivial entanglement in proteins [1], many instances of knotted and slipknotted proteins have been reported
A few hundred of the structures currently deposited in the Protein Data Bank (PDB) are known to contain knots [2,3,4,5,6,7,8,9,10,11] or, more precisely, physical knots
On the other hand, starting from the work of Wallin et al on the trefoil-knotted YibK [30], it has been known that the folding efficiency in coarse-grained models of knotted proteins can be dramatically enhanced by specific sets of non-native interactions [30,35,38]
Summary
Since the 1994 first survey of non-trivial entanglement in proteins [1], many instances of knotted and slipknotted proteins have been reported. On the other hand, starting from the work of Wallin et al on the trefoil-knotted YibK [30], it has been known that the folding efficiency in coarse-grained models of knotted proteins can be dramatically enhanced by specific sets of non-native interactions [30,35,38] Motivated by these earlier studies, we have taken advantage of recent theoretical and computational developments in advanced sampling techniques of productive folding pathways and used them to characterize the detailed folding pathway of a short trefoil-knotted protein using a realistic atomistic force field. We review and revisit the results obtained with this approach and compare them, within a common interpretative framework, with results from Monte Carlo (MC) simulations based on coarsegrained models using both purely native and native-centric potentials From the analysis, it emerges that, for at least two knotted proteins, non-native interactions arguably play a crucial role in steering the formation of the native topology and in establishing the weight of specific pathways. We investigate the folding of two other evolutionarily related proteins, one of which displays a knot that is missing in the other
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