Protonation-induced stereoisomerism in nicotine: Conformational studies using classical (AMBER) and ab initio (Car-Parrinello) molecular dynamics

Philip S. Hammond, Yudong Wu, Rebecca Harris, Todd J. Minehardt, Roberto Car, Jeffrey D. Schmitt

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

A variety of biologically active small molecules contain prochiral tertiary amines, which become chiral centers upon protonation. S-nicotine, the prototypical nicotinic acetylcholine receptor agonist, produces two diastereomers on protonation. Results, using both classical (AMBER) and ab initio (Car-Parrinello) molecular dynamical studies, illustrate the significant differences in conformational space explored by each diastereomer. As is expected, this phenomenon has an appreciable effect on nicotine's energy hypersurface and leads to differentiation in molecular shape and divergent sampling. Thus, protonation induced isomerism can produce dynamic effects that may influence the behavior of a molecule in its interaction with a target protein. We also examine differences in the conformational dynamics for each diastereomer as quantified by both molecular dynamics methods.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalJournal of Computer-Aided Molecular Design
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2005

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

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