Conformational selection in protein binding and function

TL;DR

This review discusses how conformational selection and induced fit are interconnected mechanisms in protein binding, emphasizing the importance of timescale separation and experimental methods like NMR and FRET in characterizing these processes.

Contribution

It unifies conformational selection and induced fit as complementary processes, highlighting the role of timescale separation and proposing experimental approaches for their distinction.

Findings

Conformational selection involves pre-existing protein conformations prior to binding.

Timescale separation allows decoupling of binding and conformational changes.

Experimental methods can distinguish between conformational selection and induced fit.

Abstract

Protein binding and function often involves conformational changes. Advanced NMR experiments indicate that these conformational changes can occur in the absence of ligand molecules (or with bound ligands), and that the ligands may 'select' protein conformations for binding (or unbinding). In this review, we argue that this conformational selection requires transition times for ligand binding and unbinding that are small compared to the dwell times of proteins in different conformations, which is plausible for small ligand molecules. Such a separation of timescales leads to a decoupling and temporal ordering of binding/unbinding events and conformational changes. We propose that conformational-selection and induced-change processes (such as induced fit) are two sides of the same coin, because the temporal ordering is reversed in binding and unbinding direction. Conformational-selection processes can be characterized by a conformational excitation that occurs prior to a binding or unbinding event, while induced-change processes exhibit a characteristic conformational relaxation that occurs after a binding or unbinding event. We discuss how the ordering of events can be determined from relaxation rates and effective on- and off-rates determined in mixing experiments, and from the conformational exchange rates measured in advanced NMR or single-molecule FRET experiments. For larger ligand molecules such as peptides, conformational changes and binding events can be intricately coupled and exhibit aspects of conformational-selection and induced-change processes in both binding and unbinding direction.