Abstract
SummaryAllostery is a pervasive mechanism that regulates protein activity through ligand binding at a site different from the orthosteric site. The universality of allosteric regulation complemented by the benefits of highly specific and potentially non-toxic allosteric drugs makes uncovering allosteric sites invaluable. However, there are few computational methods to effectively predict them. Bond-to-bond propensity analysis has successfully predicted allosteric sites in 19 of 20 cases using an energy-weighted atomistic graph. We here extended the analysis onto 432 structures of 146 proteins from two benchmarking datasets for allosteric proteins: ASBench and CASBench. We further introduced two statistical measures to account for the cumulative effect of high-propensity residues and the crucial residues in a given site. The allosteric site is recovered for 127 of 146 proteins (407 of 432 structures) knowing only the orthosteric sites or ligands. The quantitative analysis using a range of statistical measures enables better characterization of potential allosteric sites and mechanisms involved.
Highlights
Proteins are ubiquitous in all aspects of cellular life where they fulfil crucial functions, while their malfunction could result in disease states.[1,2] By 2017, 70% of small molecule drugs on the market targeted four types of proteins, namely protein kinases, ion channels, rhodopsin-like G protein-coupled receptors, and nuclear hormone receptors.[3]
Proteins with annotated orthosteric residues, allosteric residues, and ligands were collected from the ASBench and Allosteric Database (ASD) databases, as described in method details, which resulted in 118 structures of 113 distinct allosteric proteins
Bond-to-bond propensity analysis utilizes the orthosteric ligand as the perturbation source to mimic the ligand-binding event[57] and to identify regions on the protein that are functionally coupled to the orthosteric site
Summary
Proteins are ubiquitous in all aspects of cellular life where they fulfil crucial functions, while their malfunction could result in disease states.[1,2] By 2017, 70% of small molecule drugs on the market targeted four types of proteins, namely protein kinases, ion channels, rhodopsin-like G protein-coupled receptors, and nuclear hormone receptors.[3]. Prolonged exposure to the drugs results in drug resistance, through either modifications of the drug molecules[7] or changes to the orthosteric sites.[8,9,10,11,12] orthosteric drugs act as complete inhibitors or activators rather than modulators of proteins, so their therapeutic effect may not be the most optimal.[10]
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