Evidence for a shape-based recognition of odorants in vivo in the human nose from an analysis of the molecular mechanism of lily-of-the-valley odorants detection in the Lilial and Bourgeonal family using the C/Si/Ge/Sn switch strategy

Abstract

We performed an analysis of possible mechanisms of ligand recognition in the human nose. The analysis is based on in vivo odor threshold determination and in vitro Ca2+ imaging assays with a C/Si/Ge/Sn switch strategy applied to the compounds Lilial and Bourgeonal, to differentiate between different molecular mechanisms of odorant detection. Our results suggest that odorant detection under threshold conditions is mainly based on the molecular shape, i.e. the van der Waals surface, and electrostatics of the odorants. Furthermore, we show that a single olfactory receptor type is responsible for odor detection of Bourgeonal at the threshold level in humans in vivo. Carrying out a QM analysis of vibrational energies contained in the odorants, there is no evidence for a vibration-based recognition.

Development of Novel Silyl Cyanocinnamic Acid Derivatives as Metabolic Plasticity Inhibitors for Cancer Treatment

“…Further, crystal structure comparison of silicon analogues of known protein agonists show nearly identical binding topologies 43 . Docking poses and calculated energies have also been shown to be very similar for silicon analogues 44 . For these reasons and more practically because Vina is not internally parameterized for Si, we chose to substitute carbon in its place in the current study.…”

Estimation of Protein–Ligand Unbinding Kinetics Using Non-Equilibrium Targeted Molecular Dynamics Simulations

“…45 Ligand charge states were selected according to literature pka values. 46,47 In case of compounds 1j and 2a-k, in which protonable nitrogen atoms are found close to Asp93 and thus potentially could exhibit a different pka due to formation of salt bridges and/or strong hydrogen bonds, we performed QM calculations to obtain the correct protonation state: following earlier works, 46 we extracted the Asp93 side chain, appropriate ring fragments of the ligands carrying the protonable nitrogen atoms and water molecules between ligand fragments and the Asp93 side chain. In addition, we extracted a water molecule far from the binding site to carry an excess proton to keep the QM box charge neutral if necessary.…”

Status of the Vibrational Theory of Olfaction

“…Finally, though very narrowly, they find that the VTO is capable of chiral recognition under biological conditions. In a series of papers, Kraft et al examinedthrough both in vivo calcium ion imagining and computational methods-the validity of the "shape-based" theory of olfaction by examining the response to several Group 14-for-carbon substitution of the t-butyl functional group in the lilal and Bourgeonal odorants [128][129][130]. As these authors state, the benefit of this substitution series is that it maintains the molecular geometry while increasing the hydrophobic bulk of the molecule.…”

“…The free energy changes seen in the docking calculations with respect to the increasing hydrophobic bulk do match those results. It was finally determined that olfaction was largely based on van der Waals (VDW) surface and electrostatic surface properties, finding no evidence that the VTO played any role in olfaction [130].…”