Conformational Proofreading: The Impact of Conformational Changes on the Specificity of Molecular Recognition

TL;DR

This paper presents a statistical-mechanics model showing that conformational changes in molecules can enhance recognition specificity by acting as a proofreading mechanism, with optimal specificity achieved through slight conformational mismatches.

Contribution

It introduces a simple model linking molecular conformation and flexibility to recognition specificity, revealing conformational proofreading as a potential evolutionary advantage.

Findings

Optimal specificity occurs with slight conformational mismatch.

Conformational deformations improve selectivity.

The model suggests evolution favors conformational proofreading mechanisms.

Abstract

To perform recognition, molecules must locate and specifically bind their targets within a noisy biochemical environment with many look-alikes. Molecular recognition processes, especially the induced-fit mechanism, are known to involve conformational changes. This arises a basic question: does molecular recognition gain any advantage by such conformational changes? By introducing a simple statistical-mechanics approach, we study the effect of conformation and flexibility on the quality of recognition processes. Our model relates specificity to the conformation of the participant molecules and thus suggests a possible answer: Optimal specificity is achieved when the ligand is slightly off target, that is a conformational mismatch between the ligand and its main target improves the selectivity of the process. This indicates that deformations upon binding serve as a conformational proofreading mechanism, which may be selected for via evolution.