How to distinguish conformational selection and induced fit based on chemical relaxation rates

TL;DR

This paper provides a comprehensive theoretical framework to differentiate conformational selection from induced fit in protein binding by analyzing chemical relaxation rates across all concentrations, enabling more accurate interpretation of experimental data.

Contribution

It introduces general formulas for chemical relaxation rates applicable at all concentrations, allowing distinction between binding mechanisms and extraction of conformational transition rates.

Findings

Derived formulas distinguish conformational selection from induced fit.

Applicable at all protein and ligand concentrations, not just pseudo-first-order.

Enables extraction of conformational transition rates from relaxation data.

Abstract

Protein binding often involves conformational changes. Important questions are whether a conformational change occurs prior to a binding event ('conformational selection') or after a binding event ('induced fit'), and how conformational transition rates can be obtained from experiments. In this article, we present general results for the chemical relaxation rates of conformational-selection and induced-fit binding processes that hold for all concentrations of proteins and ligands and, thus, go beyond the standard pseudo-first-order approximation of large ligand concentration. These results allow to distinguish conformational-selection from induced-fit processes - also in cases in which such a distinction is not possible under pseudo-first-order conditions - and to extract conformational transition rates of proteins from chemical relaxation data.