Hammond Philip S, Wu Yudong, Harris Rebecca, Minehardt Todd J, Car Roberto, Schmitt Jeffrey D
Targacept, Inc., 200 East First Street, Suite 300, Winston-Salem, NC 27101-4165, USA.
J Comput Aided Mol Des. 2005 Jan;19(1):1-15. doi: 10.1007/s10822-005-0096-7.
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.
多种具有生物活性的小分子含有前手性叔胺，质子化后会成为手性中心。S-尼古丁是典型的烟碱型乙酰胆碱受体激动剂，质子化时会产生两种非对映异构体。使用经典（AMBER）和从头算（Car-Parrinello）分子动力学研究的结果表明，每种非对映异构体在构象空间上存在显著差异。正如预期的那样，这种现象对尼古丁的能量超曲面有明显影响，并导致分子形状的差异和不同的采样。因此，质子化诱导的异构化可以产生动态效应，可能会影响分子与靶蛋白相互作用时的行为。我们还通过两种分子动力学方法量化了每种非对映异构体在构象动力学上的差异。
