title: Protonation-induced stereoisomerism in nicotine: conformational studies using classical (AMBER) and ab initio (Car-Parrinello) molecular dynamics.
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.
authors.affiliation: Targacept, Inc., 200 East First Street, Suite 300, Winston-Salem, NC 27101-4165, USA. phil.hammond@targacept.com
authors.forename: Philip S
authors.initials: PS
authors.lastname: Hammond
authors.forename: Yudong
authors.initials: Y
authors.lastname: Wu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harris
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Minehardt
authors.forename: Roberto
authors.initials: R
authors.lastname: Car
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Schmitt
mesh_terms: D008968:Molecular Conformation; D009538:Nicotine / Q000737:chemistry*; D011522:Protons; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D013237:Stereoisomerism
chemical_list: D011522:Protons; D009538:Nicotine