Essential sub-networks based on contact strength reveal folding kinetics

TL;DR

This study introduces a weighted relative contact order (RCO) based on contact strength to better predict protein folding kinetics, highlighting the importance of hydrophobic interactions and essential sub-networks in folding processes.

Contribution

It presents a novel weighted RCO incorporating contact strength and essential sub-networks, improving understanding of sequence and interaction effects on folding kinetics.

Findings

Weighted RCO correlates with folding rates similarly to traditional RCO.

Hydrophobic interactions are crucial for two-state protein folding.

Essential sub-networks reveal differences in mutant folding behaviors.

Abstract

It has been observed that the topology of the native state is an important determinant of protein folding kinetics and there is a significant correlation between folding rate and relative contact order (RCO) in two-state small single-domain proteins. However, as a pure topological property, RCO does not take into account residue interactions that also play an important role in folding kinetics. Using the inter-residue statistical contact potentials, we introduce weight into the residue network of contacts, and therefore define a weighted RCO. Using the weighted RCO, we can capture the folding kinetics of proteins having the same topology, but different sequence information. By constructing essential sub-networks based on the strength of the pairwise interactions, we are able to deduce the features of sequences redundant for folding events. We perform an analysis on 48 two-state proteins and the ultrafast-folding proteins, as well as mutants of the protein CI2, protein G, and protein L. Our results indicate that (i) both the weighted RCO of original residue network and that of essential sub-networks have significant correlations with the folding rate like RCO; (ii) the folding rate is critically dependent on the hydrophobic interactions for two-state folding; and (iii) the sub-networks distinguish the folding rate differences of the mutants and reveal the folding preferences of proteins.