Investigating determinants of sweetness of sweet molecules

Abstract

People suffering from various ailments are not able to consume sugar. Therefore, alternative sweeteners are desired, but most of them have many side effects, particularly on prolonged usage. This necessitates the need to understand the molecular mechanism of sweetness. Sweetness is effected by recognition of sweet molecule by a receptor present in taste buds called human Sweet Taste Receptor. There exists a plethora of molecules tasting sweet having diverse chemical and structural nature. It includes a few sweet proteins too. There are many theories to explain this, most commonly accepted one is AH-B-X theory. Efforts to newlinedesign peptides based on this turned out to be tasteless, indicating some different sweetness mechanism for them. hSTR is a huge dimeric protein, each subunit containing more than 800 residues. This makes an arduous task to predict the 3D structure and identify the determinants of sweetness. We have used a multistep strategy for same. First we predicted domain wise structure and then newlinecombine them to build the complete subunits. This followed docking and classification of newlinesweet molecules and proteins based on their site of interaction. Reliability of structures was assessed by comparing with experimental data. Effect of metal ions and point mutations on sweetness was studied to identify crucial residues and pharmacophore. No common pharmacophores could be identified. Residues responsible for stability of hSTR were identified.This explains how a wide variety of molecules (even proteins having no sequence or conformational similarity) can elicit sweet response. Group of molecules having common active sites of interaction, even they do not have any common pharmacophore.