From sequence and structure to function: Odorant-binding proteins

Abstract

The olfactory system can detect and discriminate among environmental odorants that play a crucial role in various insect behaviors. Among them, odorant-binding proteins (OBPs) have been considered important components of the olfactory apparatus in recognising odorants. OBPs undergo conformational changes due to pH changes and ligand binding altering their interactions with odorants. My thesis aims to understand the function of odorant-binding proteins in the context of the sequence, structure and evolution across insect orders and mammals. A pipeline was constructed to integrate genomics and machine-learning approaches to predict whether a protein sequence belongs to the OBP subfamily or other classes. In the hemolymph of malaria causing female Anopheles gambiae, OBP1 and OBP4 may form heterodimers to facilitate perception of indole, different from those of the individual proteins, thus increasing the number of detectable odours. Our work showed that a decrease in pH is associated with a concomitant reduction in the inter and intra-monomeric dynamic fluctuations of the indole-bound heterodimer. Further work in my thesis has identified a set of naturally derived compounds as inhibitors to heterodimeric OBP-indole and monomeric OBP-indole complexes in mosquitoes through computational virtual screening and molecular dynamic simulations. Furthermore, protein-ligand docking, molecular dynamic (MD) simulations and thermal binding affinity analysis of OBP isoforms from the buffalo nasal epithelium revealed four residues (Phe69, Phe104, Asn118 and Phe134) from OBP1a, contributed strong binding affinities towards two sex pheromones, specifically oleic acid and p-cresol. The predicted protein sequences further helped in understanding evolutionary relationships among various subfamilies of OBPs.