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

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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.

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Abbreviations

aiMD:

ab initio molecular dynamics

ACh:

acetylcholine

AChBP:

acetylcholine binding protein

DFT:

density functional theory

LGIC:

ligand-gated ion channels

MM:

molecular mechanics

nAChR:

nicotinic acetylcholine receptors

QM:

quantum mechanics

QSAR:

quantitative structure activity relationships

SE:

semi-empirical.

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Authors and Affiliations

  1. Targacept, Inc., 200 East First Street, Suite 300, Winston-Salem, NC, 27101-4165, USA

    Philip S. Hammond, Rebecca Harris & Jeffrey D. Schmitt

  2. Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA

    Yudong Wu & Roberto Car

  3. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA

    Yudong Wu

  4. N Space Labs, Inc, 39 W. 14th St, Suite 404, New York, NY, 10011, USA

    Todd J. Minehardt

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  1. Philip S. Hammond
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  3. Rebecca Harris
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  4. Todd J. Minehardt
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Correspondence to Philip S. Hammond.

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Hammond, P.S., Wu, Y., Harris, R. et al. Protonation-induced stereoisomerism in nicotine: Conformational studies using classical (AMBER) and ab initio (Car–Parrinello) molecular dynamics. J Comput Aided Mol Des 19, 1–15 (2005). https://doi.org/10.1007/s10822-005-0096-7

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