Tang Pei, Xu Yan
Departments of Anesthesiology and Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16035-40. doi: 10.1073/pnas.252522299. Epub 2002 Nov 18.
Interactions of volatile anesthetics with the central nervous system are characterized by low yet specific binding affinities. Although neurotransmitter-gated ion channels are considered the primary anesthetic targets, the mechanism of action at the molecular level remains elusive. We consider here the theoretical implications of channel dynamics on anesthetic action in a simplified membrane-channel system. Large-scale 2.2-ns all-atom molecular dynamics simulations were performed to study the effects of halothane, a clinical anesthetic, on a gramicidin A (gA) channel in a fully hydrated dimyristoyl phosphatidylcholine membrane. In agreement with experimental results, anesthetics preferentially target the anchoring residues at the channel-lipid-water interface. Although the anesthetic effect on channel structure is minimal, the presence of halothane profoundly affects channel dynamics. For 2.2-ns simulation, the rms fluctuation of gA backbone in the lipid core increases from approximately equal 1 A in the absence of anesthetics to approximately equal 1.5 A in the presence of halothane. Autocorrelation analysis reveals that halothane (i) has no effect on the subpicosecond librational motion, (ii) prolongs the backbone autocorrelation time in the 10- to 100-ps time scale, and (iii) significantly decreases the asymptotic values of generalized order parameter and correlation time of nanosecond motions for the inner but not the outer residues. The simulation results discount the viewpoint of a structure-function paradigm that overrates the importance of structural fitting between general anesthetics and yet-unidentified hydrophobic protein pockets. Instead, the results underscore the global, as opposed to local, effects of anesthetics on protein dynamics as the underlying mechanisms for the action of general anesthetics and possibly of other low-affinity drugs.
挥发性麻醉剂与中枢神经系统的相互作用具有低但特异性的结合亲和力。尽管神经递质门控离子通道被认为是主要的麻醉靶点，但分子水平的作用机制仍不清楚。我们在此考虑通道动力学在简化膜通道系统中对麻醉作用的理论影响。进行了大规模的2.2纳秒全原子分子动力学模拟，以研究临床麻醉剂氟烷对完全水合的二肉豆蔻酰磷脂酰胆碱膜中短杆菌肽A（gA）通道的影响。与实验结果一致，麻醉剂优先靶向通道 - 脂质 - 水界面处的锚定残基。尽管麻醉剂对通道结构的影响最小，但氟烷的存在深刻影响通道动力学。对于2.2纳秒的模拟，脂质核心中gA主链的均方根波动从无麻醉剂时的约等于1埃增加到有氟烷时的约等于1.5埃。自相关分析表明，氟烷（i）对亚皮秒级的摆动运动没有影响，（ii）在10到100皮秒的时间尺度上延长了主链自相关时间，并且（iii）显著降低了内部而非外部残基的广义序参量渐近值和纳秒级运动的相关时间。模拟结果不支持结构 - 功能范式的观点，该观点高估了全身麻醉剂与尚未确定的疏水蛋白口袋之间结构匹配的重要性。相反，结果强调了麻醉剂对蛋白质动力学的全局而非局部影响，这是全身麻醉剂以及可能其他低亲和力药物作用的潜在机制。
