Molecular mechanics-driven comparative analysis of protein-ligand binding pockets to investigate the relationship between taste perception and metabolic pathways

The sense of taste in mammals, including humans, is a complex natural mechanism that acts as a sentinel system, allowing for a quick recognition of chemicals that enter the oral cavity and the discrimination between healthy and nutritious food and substances potentially toxic or dangerous to health. This crucial ability is enabled by the key players of the sense of taste, i.e. taste receptors: these are highly specialized proteins that play the role of molecular switches for specific cellular signalling pathways, ultimately resulting in the perception of the five basic tastes: sweet, bitter, umami, salty and sour. Moreover, several studies have shown that the localization of taste receptors is not limited to the oral cavity only, but is rather widespread throughout the human body, including the gastrointestinal tract and the central nervous system, where a direct sensation of taste is not evoked. In fact, in such tissues they are thought to serve a different set of functions revolving around nutrition and food absorption. In this context, where the interaction between taste receptors and tastants is not exclusive to the gustatory system alone, the present work is focused on a high-level analysis, starting from the molecular-level characterization of the binding site of the human sweet taste receptor, a class-C GPCR, in complex with its tastant agonist sucrose, to perform a similarity search to scan for the conserved tastant-binding site residues in the currently solved proteome, with the goal of shedding light on the putative function of food molecules within domains and pathways that are external to the gustatory system. In order to identify the proteins of greatest interest and significance, two successive filtering steps were performed, the first one relying on Solvent-Accessible Surface Area (SASA) calculations to extract proteins with an exposed-surface binding site with a shape similar to that present in the sweet receptor; the second step consisted in Molecular Docking calculations of sweet ligands to the proteins extracted from the first step, to restrict the analysis to those with binding affinity values above a fixed threshold. Such proteins were analyzed from a proteomic perspective, and it was observed that most of them are involved in enzymatic activities, e.g. hydrolases, oxidoreductases, or transferases, as well as in various biological processes that range from nucleocytoplasmic transport, biosynthesis of nitrogenous bases, up to post-translational modifications that control protein activity. The results obtained regarding the conservation of the binding site, the nature and role of the candidate proteins discovered, and the methodologies and platforms adopted in the present work can be used as a basis for future studies focused on the use of tastants and corresponding receptors as models for the engineering of drugs for the treatment of food-related diseases and disorders.