Driving Protein Conformational Cycles in Physiology and Disease: “Frustrated” Amino Acid Interaction Networks Define Dynamic Energy Landscapes

Abstract

A general framework by which dynamic interactions within a protein will promote the necessary series of structural changes, or “conformational cycle,” required for function is proposed. It is suggested that the free‐energy landscape of a protein is biased toward this conformational cycle. Fluctuations into higher energy, although thermally accessible, conformations drive the conformational cycle forward. The amino acid interaction network is defined as those intraprotein interactions that contribute most to the free‐energy landscape. Some network connections are consistent in every structural state, while others periodically change their interaction strength according to the conformational cycle. It is reviewed here that structural transitions change these periodic network connections, which then predisposes the protein toward the next set of network changes, and hence the next structural change. These concepts are illustrated by recent work on tryptophan synthase. Disruption of these dynamic connections may lead to aberrant protein function and disease states.

Substitution of a Surface-Exposed Residue Involved in an Allosteric Network Enhances Tryptophan Synthase Function in Cells

“…Instead, these models focus on changes within the conformational ensemble using a free energy landscape framework (Motlagh et al, 2014). However, we believe these views of allostery can be compatible (D'Amico et al, 2020). In fact, the CHESCA approach identifies network residues as those being involved in the same conformational change (Selvaratnam et al, 2011), but does not necessitate that there are direct interactions between such residues.…”

“…For enzyme assays, the IGP concentration was determined using ε 5.54 mM −1 cm −1 . Assays of the αTS subunit alone were performed using a previously described assay (Creighton, 1970;Lane and Kirschner, 1991), which utilizes a coupled reaction scheme as follows:…”