The Role of Conformational Changes in Molecular Recognition

Conformational changes of molecules are crucial elements in many biochemical processes, and also in molecular recognition. Here, we present a novel exact mathematical equation for the binding free energy of a receptor–ligand pair. It shows that the energetic contribution due to conformational changes upon molecular recognition is defined by the so-called Kullback–Leibler (KL) divergence between the probability distributions of the conformational ensemble of the biomolecule in the bound and free states. We show that conformational changes always contribute positively to the change in free energy and therefore disfavor the association process. Using the example of ligands binding to a flexible cavity of T4 lysozyme, we illustrate that, due to enthalpy–entropy compensation, the conformational entropy is a misleading quantity for assessing the conformational contribution to the binding free energy, in contrast to the KL divergence, which is the correct quantity to use in this context

How Molecular Conformational Changes Affect Changes in Free Energy

A simple quantitative relationship between the molecular conformational changes and the corresponding changes in the free energy is presented. The change in free energy is the sum of that part of the enthalpic change that is due to the externally applied work (perturbation) and of that part of the entropic change, termed dissipative entropy, that is related to the conformational changes. The dissipative entropy is equivalent to the relative entropy, a concept from information theory, between the distributions of the conformations in the initial and the final states. The remaining change in entropy (nondissipative) cancels exactly with the remaining enthalpic change. The calculation of the dissipative entropy is demonstrated to pose the main difficulty in free energy computation. The straightforward decomposition of the dissipative entropy into contributions from different parts of the system promises to improve the understanding of the role of conformational changes in biochemical reactions