Heterodimer binding scaffolds recognition via the analysis of kinetically hot residues

TL;DR

This paper introduces an algorithm using the Gaussian Network Model to identify binding patches and scaffolds in heterodimer proteins by analyzing kinetically hot residues, showing promising results especially for chains with high length ratios.

Contribution

The paper presents a novel GNM-based method for recognizing heterodimer binding scaffolds through kinetically hot residues, with adjustable mode selection for improved accuracy.

Findings

The GNM approach performs well on heterodimers with high chain length ratios.

In some cases, GNM predictions are comparable or better than statistical potentials.

Interacting chains often exhibit rigid or flexible complementary behaviors.

Abstract

Physical interactions between proteins are often difficult to decipher. The aim of this paper is to present an algorithm designed to recognize binding patches and supporting structural scaffolds of interacting heterodimer protein chains using the Gaussian Network Model (GNM). The recognition is based on the (self)adjustable identification of kinetically hot residues, i.e., residues with highest contributions to the weighted sum of fastest modes per chain extracted via GNM, and their connection to possible binding scaffolds. The algorithm adjusts the number of modes used in the GNM's weighted sum calculation using the ratio of predicted and expected numbers of target residues (contact and first layer residues). This approach produces very good results when applied to chains forming heterodimers, especially with dimers with high chain length ratios. The protocol's ability to recognize near native decoys was compared to the ability of the statistical potential of Lu and Skolnick using the Sternberg and Vakser decoy dimers sets. The statistical potential produced better overall results, but in a number of cases its predicting ability was comparable, or even worse than the ability of the adjustable GNM approach. The results presented in this paper suggest that in heterodimers, at least one partnering chain has interacting scaffold determined by the immovable kinetically hot residues. In many cases interacting chains (especially if being of noticeably different sizes), either behave as rigid lock and key, or exhibit opposite dynamic behaviors. While the binding surface of one of the chains is rigid and stable, its partner's interacting scaffold is more flexible and adaptable. Authors note: The approach described here was initially given as a rough draft in 2013 [1]. The next manuscript will describe the behavior of protein dimers incorrectly characterized with the present approach.