Energetic redistribution in allostery to execute protein function

Abstract

A perturbation at one site of the protein could cause an effect at a distant site. This important biological phenomenon, termed the “allosteric effect,” is essential for protein regulation and cell signaling, playing an important role in cellular function. Its fundamental functional significance has inspired numerous works aiming to understand how allostery works. Allostery can involve large, or unobserved, subtle (mainly side-chain) conformational changes (1). Conformational changes are driven by enthalpy. The term “dynamic allostery” was coined by Cooper and Dryden in the early 1980s to describe allostery “even in the absence of a macromolecular conformational change” (2). Cooper and Dryden argued that dynamic allostery is primarily an entropy effect. However, numerous works have been published over the last 20 y taking “dynamic allostery” to imply a complete absence of conformational change because the authors did not observe such changes (1). Importantly, “dynamic allostery” without observable conformational changes is still ruled by a population shift between two “distinct” states where a new energetic redistribution favorable for the allosteric (functional) state is either dominated by entropy, enthalpy, or both. Few studies questioned whether enthalpy plays a role in dynamic allostery as well (1). In PNAS, Kumawat and Chakrabarty (3) demonstrate that indeed even in dynamic allostery enthalpy plays a role by redistributing internal energies, especially electrostatic interaction energies, among residues upon perturbation (Fig. 1). Fig. 1. The scheme of the electrostatic basis of dynamic allostery in the PDZ3 domain protein. Dynamic allostery has no significant conformational change. Upon binding of the peptide (CRIPT), there is no significant enthalpy change, but Kumawat and Chakrabarty (3) reported a redistribution of the electrostatic energies. Such redistribution may propagate to other PDZ domains for the proteins to execute their function. Electrostatics is an established player in function. Decades ago, Warshel (4 … [↵][1]1To whom correspondence may be addressed. Email: jin.liu{at}unthsc.edu or NussinoR{at}mail.nih.gov. [1]: #xref-corresp-1-1