Sequence and structural patterns detected in entangled proteins reveal the importance of co-translational folding

TL;DR

This study uncovers specific sequence and structural patterns in proteins that facilitate co-translational folding and manage backbone entanglement, highlighting their prevalence and potential role in efficient protein folding.

Contribution

It reveals the existence and characteristics of entanglement-related motifs in proteins and their implications for folding mechanisms, a novel insight into protein topology.

Findings

Entangled loops are often closed by weakly bound amino acids.

Such loops tend to form late in folding to avoid kinetic traps.

These motifs are present in 32% of analyzed proteins.

Abstract

Proteins must fold quickly to acquire their biologically functional three-dimensional native structures. Hence, these are mainly stabilized by local contacts, while intricate topologies such as knots are rare. Here, we reveal the existence of specific patterns adopted by protein sequences and structures to deal with backbone self-entanglement. A large scale analysis of the Protein Data Bank shows that loops significantly intertwined with another chain portion are typically closed by weakly bound amino acids. Why is this energetic frustration maintained? A possible picture is that entangled loops are formed only toward the end of the folding process to avoid kinetic traps. Consistently, these loops are more frequently found to be wrapped around a portion of the chain on their N-terminal side, the one translated earlier at the ribosome. Finally, these motifs are less abundant in natural native states than in simulated protein-like structures, yet they appear in 32% of proteins, which in some cases display an amazingly complex intertwining.