Conformational analysis of d-tubocurarine: Implications for minimal dimensions of its binding site within ion channels |
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Authors: | Boris S. Zhorov Nina B. Brovtsyna |
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Affiliation: | (1) Pavlov Institute of Physiology of the Russian Academy of Sciences, B-034 St. Petersburg, Russia;(2) Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, K-223 St. Petersburg, Russia |
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Abstract: | All the minimum-energy conformations of d-tubocurarine were calculated by the method of molecular mechanics. The energy was minimized from 413 closed forms of the 18-member ring. The set of minimum-energy conformations includes 10 forms with energies less than 6 kcal/mol from the most stable one. Among the four lowest minimum-energy conformations, two forms correspond to those known from X-ray studies, whereas two conformations were not detected experimentally earlier. The flexibility of d-tubocurarine was estimated by calculating six paths of interconversion between the four lowest minimum-energy conformations. Using a molecular graphics technique, it was found that the most extended minimum-energy conformation of d-tubocurarine may fit in an ion channel of a rectangular profile of 8.7 × 11.2 Å, while one tetrahydroisoquinoline head may fit a profile as small as 6.9 × 11.0 Å. A possible model of d-tubocurarine location within the ion channel of the neuronal nicotinic acetylcholine receptor is suggested. |
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Keywords: | Tubocurarine Conformation Ionchannel Mechanism of blockade Acetylcholine receptor |
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