Insight into the human sour taste receptor: a molecular modelling study on the Otopetrin family candidates

Five canonical tastes, i.e. bitter, sweet, umami (amino acids), salty and sour (acids) are detected by animals as diverse as fruit flies and humans, consistent with a near-universal drive to consume fundamental nutrients and to avoid toxins or other harmful compounds. In the last few years a high number of scientific sign of progress have been made in the studying and discovery of the molecular mechanisms behind the sweet, bitter and umami tastes whereas sour taste mechanisms are still poorly understood and investigated. Only recently, few studies pointed out that the sour transduction mechanism may be mediated by the Otopetrins, a family of trans-membrane proteins which are deemed to play an important role in the H+ permeation through the ion channel. However, the lack of a three-dimensional structure of the human Otopetrin greatly limits the possibility of in silico molecular investigation able to shed light on the molecular mechanisms underlying the sour receptor function. Therefore, this work aims to create and characterise a human Otopetrin three-dimensional model starting from recently solved non-human Otopetrins. Human atomistic model has been created using several types of structure prediction software, including classical homology modelling techniques, threading-based protocols and machine learning-driven ones. The best model was chosen after a rational structural comparison employing state-of-the-art analysis tools. The refined receptor was prepared for future molecular dynamics simulation in a physiological environment including a cellular membrane. Lastly, the interactions between the best model obtained (target) with a set of acid molecules (ligands) have been investigated using molecular docking to elucidate the mechanisms of ligand-receptor binding. The results obtained regarding the creation of the three-dimensional human model, the role of the refined receptor investigated, together with the physiological system optimised in the present work can be used as a basis for future studies focused on molecular mechanisms at the basis of sour taste transduction.