Several diseases such as schizophrenia, Tourette's syndrome, Parkinson's, and Alzheimer's are caused by improper regulation of the neurotransmitter dopamine. Native a-conotoxin MII (a-CTxMII), a neurotoxic peptide from the venom of the marine cone snail, is a potent competitive neuronal nicotinic acetylcholine receptor (nAChRs) antagonist. Neuronal nAChRs are known to regulate dopamine release at nerve cells in response to nicotine and/or acetylcholine binding. In particular the a6�2 subunit is believed to reside at the presynapse in the nigrostriatal pathway and is suspected to be involved in motor behavior. The antagonistic property of a-CTxMII makes it an attractive starting point for developing medications for neurological disorders. Unfortunately, a-CTxMII is unable to differentiate between the a3�2 or a6�2 subunits of nAChRs resulting in system wide inhibition of dopamine release. It has been shown that the His12 residue is critical for the binding of a-CTxMII to the a6�2 subunit.  The a-CTxMII-E11A shows specificity towards the a6�2 subunit of nAChRs and therefore represents a first generation of specific nAChRs antagonists. Computational evaluation of the amino acid environment in a-CTxMII and several variants (E11A, and N5R-E11A-H12K) are being conducted in order to reveal the electrostatic environment, resulting pKa and the impact of the protonation states on toxicity.

Computational studies of conotoxins as nicotinic acetylcholine receptor (nAChRs) antagonists

243rd National Meeting (2012)

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