Advances of Predicting Allosteric Mechanisms Through Protein Contact in New Technologies and Their Application.

Abstract

Allostery is an intriguing phenomenon wherein the binding activity of a biological macromolecule is modulated via non-canonical binding site, resulting in synchronized functional changes. The mechanics underlying allostery are relatively complex and this review is focused on common methodologies used to study allostery, such as X-ray crystallography, NMR spectroscopy, and HDXMS. Different methodological approaches are used to generate data in different scenarios. For example, X-ray crystallography provides high-resolution structural information, NMR spectroscopy offers dynamic insights into allosteric interactions in solution, and HDXMS provides information on protein dynamics. The residue transition state (RTS) approach has emerged as a critical tool in understanding the energetics and conformational changes associated with allosteric regulation. Allostery has significant implications in drug discovery, gene transcription, disease diagnosis, and enzyme catalysis. Enzymes' catalytic activity can be modulated by allosteric regulation, offering opportunities to develop novel therapeutic alternatives. Understanding allosteric mechanisms associated with infectious organisms like SARS-CoV and bacterial pathogens can aid in the development of new antiviral drugs and antibiotics. Allosteric mechanisms are crucial in the regulation of a variety of signal transduction and cell metabolism pathways, which in turn govern various cellular processes. Despite progress, challenges remain in identifying allosteric sites and characterizing their contribution to a variety of biological processes. Increased understanding of these mechanisms can help develop allosteric systems specifically designed to modulate key biological mechanisms, providing novel opportunities for the development of targeted therapeutics. Therefore, the current review aims to summarize common methodologies that are used to further our understanding of allosteric mechanisms. In conclusion, this review provides insights into the methodologies used for the study of allostery, its applications in in silico modeling, the mechanisms underlying antibody allostery, and the ongoing challenges and prospects in advancing our comprehension of this intriguing phenomenon.