Dodging the crisis of folding proteins with knots

TL;DR

This paper investigates how knotted proteins fold by proposing a mechanism involving slipknot intermediates, highlighting topological barriers and the role of native contacts, using coarse-grained simulations to understand complex folding pathways.

Contribution

It introduces a novel folding mechanism involving slipknot intermediates and demonstrates how topological barriers affect folding efficiency in knotted proteins.

Findings

Slipknot intermediates facilitate folding

Knotted proteins face topological barriers

Unknotted variants fold more efficiently

Abstract

Proteins with nontrivial topology, containing knots and slipknots, have the ability to fold to their native states without any additional external forces invoked. A mechanism is suggested for folding of these proteins, such as YibK and YbeA, which involves an intermediate configuration with a slipknot. It elucidates the role of topological barriers and backtracking during the folding event. It also illustrates that native contacts are sufficient to guarantee folding in around 1-2% of the simulations, and how slipknot intermediates are needed to reduce the topological bottlenecks. As expected, simulations of proteins with similar structure but with knot removed fold much more efficiently, clearly demonstrating the origin of these topological barriers. Although these studies are based on a simple coarse-grained model, they are already able to extract some of the underlying principles governing folding in such complex topologies.