Advancing the science of smell — with a hint of musk

New Yale-led research into the molecular basis of the human sense of smell may have implications for a variety of effects on mood and behavior in vertebrates.
A man smelling the cap of a bottle of expensive cologne.


Researchers have identified key molecular mechanisms at work when people smell musks, a highly valued group of fixatives used in many perfumes and colognes. The discovery may have implications for a wide range of effects on mood and behavior in vertebrates, said the scientists.

The research is the latest step in the ongoing scientific exploration of how human smell starts at the molecular level — an intricate, chemical process that has long eluded scientists. A Yale-led research group described the findings in a study published online April 9 in the journal Proceedings of the National Academy of Sciences.

Our computational structural models of olfactory receptors have guided mutagenesis experiments and provided understanding of the interactions responsible for musk binding,” said Victor Batista, a chemistry professor at Yale and one of the principal investigators for the study. Batista is also a member of the Energy Sciences Institute at Yale’s West Campus.

Batista and his colleagues are proponents of a theory that smell is initiated by specific molecular interactions between odorants and G protein coupled receptors (GPCRs) in the olfactory epithelium in the nasal cavity, triggering memories and eliciting responses based on experiences with that scent. Previous research by the group identified two olfactory receptors in humans, OR5AN1 and OR1A1, that respond to musk compounds.

Although musks are widely used in perfumes and in traditional Chinese medicine, little is known about how they work at the molecular level during olfaction. Such knowledge, note the researchers, could help advance the study of the pharmacological effects of musks.

The researchers developed structural models of OR5AN1 and OR1A1 based on quantum mechanics/molecular mechanics hybrid methods, a molecular simulation method that enables the study of chemical processes in solution and in proteins. These structural models predicted binding sites on OR5AN1 and OR1A1 for a variety of musks.

Our findings allow us to understand how olfaction works at the molecular level,” said Yale postdoctoral associate Lucky Ahmed, the study’s co-lead author.

The researchers found that OR5AN1 responds to macrocyclic and nitromusk compounds (two groups of synthetic musks), while OR1A1 responds prominently only to nitromusks. The researchers also identified amino acid residues that aid in the binding process.

The research team included scientists from Shanghai Jiao Tong University School of Medicine, the University of Albany-SUNY, the University of St. Andrews, the University of Campinas, Duke, and China Agricultural University.

Yuetian Zhang of Shanghai Jiao Tong University is the study’s other co-lead author. The other co-principal investigators are Eric Block of the University of Albany-SUNY, David O’Hagan of the University of St. Andrews, and Hanyi Zhuang of Shanghai Jiao Ton University.

Co-authors from Yale are Sivakumar Sekharan, Mehmet Ozbil and Nicholas Ten, previous members of the Batista research group.


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