Past Event: Oden Institute Seminar

Understanding signal propagation in nicotinic acetylcholine receptors

Sofia Oliveira, School of Biochemistry and Centre for Computational Chemistry, University of Bristol

Abstract

Cigarette smoking is considered, nowadays, to be a significant public health problem. Recent estimates indicate that approximately 1/4th of the world's population smokes1 and that smoking is the second most prevalent cause of death in the world2. Currently, the FDA-approved smoking cessation drugs, such as varenicline, are only moderately effective in reducing the symptoms of nicotine withdrawal and may cause undesirable side effects. Consequently, there is a growing need to develop new smoking cessation agents with improved effectiveness and tolerability. Nicotine is the major biologically psychoactive agent in tobacco, and it binds to the nicotinic acetylcholine receptors (nAChRs)3. These receptors mediate synaptic transmission in the nervous system and are therapeutic targets for various neurodegenerative diseases, psychiatric and neurodevelopmental disorders, including nicotine addiction3. Over the last decades, nAChRs have been widely explored, and our understanding of their molecular mechanisms has made extensive progress. However, despite a plethora of available structural and biochemical data, it is still not clear how ligand binding induces the conformational changes necessary to modulate the receptor’s dynamics. Answering this question requires knowledge of the dynamics of the protein and the identification of the conformational changes that take place upon ligand binding. Molecular dynamics (MD) simulations offer a highly effective method to identify, ‘assay’ and analyse functionally important motions of proteins and recently we have used a combination of equilibrium and nonequilibrium molecular dynamics simulations to map dynamic and structural changes induced by nicotine in two of the most relevant nAChRs, namely the α4β24,5 and the α74,6 subtypes. Our simulations reveal a striking pattern of communication between the agonist-binding pockets and the transmembrane domains and show the sequence of conformational changes associated with the initial steps of signal propagation.