物理化学学报 >> 2016, Vol. 32 >> Issue (4): 907-920.doi: 10.3866/PKU.WHXB201601141

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左苯丙胺在多巴胺第三受体分子通道中传输分子动力学模拟

谢炜,徐泽人,王明,徐四川*()   

  • 收稿日期:2015-11-04 发布日期:2016-04-07
  • 通讯作者: 徐四川 E-mail:sichuan@ynu.edu.cn
  • 基金资助:
    国家自然科学基金(21163024, 21563032)

Molecular Dynamics Simulation for Levo-Benzedrine to Transmit through Molecular Channels within D3R

Wei XIE,Ze-Ren XU,Ming WANG,Si-Chuan XU*()   

  • Received:2015-11-04 Published:2016-04-07
  • Contact: Si-Chuan XU E-mail:sichuan@ynu.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(21163024, 21563032)

摘要:

左旋苯丙胺(又称左苯丙胺, RAT)在临床上被用于治疗多种病症,作用在中枢神经细胞多巴胺受体上,同时它具有依赖性和成瘾性。为了探讨RAT被用作药物的药理和成瘾机制,本文用分子模拟获得RAT与多巴胺第三受体(D3R)复合蛋白优化结构,并且采用伞形样本平均力势(PMF)方法和卵磷脂脂质分子模拟生物膜,采用分子动力学模拟获得RAT在D3R结构中分子通道运动轨迹和自由能变化。RAT通过D3R结构中的功能分子通道,朝细胞外方向传输运动的自由能变化为91.4 kJ·mol-1。RAT通过D3R结构中的保护分子通道,朝细胞双层膜方向传输运动的自由能变化为117.7 kJ·mol-1。自由能数值表明RAT分子更容易通过D3R结构中的功能分子通道,发挥其功能作用,增大功能多巴胺分子的释放,导致包括依赖性和成瘾性多种功能效果。研究结果证明RAT被用作药物的药理和成瘾机制与它在多巴胺受体中的分子通道上传输动力学和机制有密切关联。

关键词: 左苯丙胺, 多巴胺第三受体, 1-棕榈酰基-2-油酰基卵磷脂, 分子动力学模拟, 自由能

Abstract:

Levo-benzedrine (also known as L-benzedrine or RAT) acts in dopamine receptors of the central nerve cell. In a clinical setting, RAT is used to treat a variety of diseases; however, it can also result in physical dependence and addiction. To investigate the pharmacology and addiction mechanism of RAT as a medication, we have obtained the optimized structure of the dopamine Ⅲ receptor (D3R) complex protein with RAT. On the basis of this structure, by using the method of potential mean force (PMF) with umbrella sampling and the simulated phospholipid bilayer membrane (also known as the POPC bilayer membrane), the molecular dynamics simulation was performed to obtain the trajectories with the changes of free energy on the structure for RAT to move along the molecular channels within D3R. The change of free energy for RAT to transfer toward the outside of the cell along the functioning molecular channel within D3R is 91.4 kJ·mol-1. The change of free energy for RAT to transfer into the POPC bilayer membrane along the protecting molecular channel within D3R is 117.7 kJ·mol-1. These results suggest that RAT is more likely to exert its molecular functions and to increase the release of functioning dopamine molecules by transferring along the functioning molecular channel within D3R, which result in a variety of functional effects by RAT including dependence and addiction. The obtained results show that the pharmacology and addiction mechanism of RAT as a medication are closely related to the molecular dynamics and mechanism for RAT to transfer along molecular channels within dopamine receptors.

Key words: L-Benzedrine, D3R, POPC, Molecular dynamics simulation, Free energy

MSC2000: 

  • O642