二芳基乙烯衍生物与DNA结合的分子动力学研究

doi:10.7503/cjcu20180837

摘要/Abstract

摘要：

基于分子动力学方法, 对2种旋转异构的二芳基乙烯(DTE, dithienylethene)衍生物(DTE1和DTE2)与不同分子结构DNA结合过程的热力学与动力学特征进行模拟, 结果发现, DTE1, DTE2与DNA分子采用小凹槽结合(MiGB)的模式结合时所需能量最低, 存在的分子间库仑能与范德华相互作用能最小, 说明该结合模式最稳定; 由于空间位阻作用, 互为旋转异构体的2个DTE衍生物与DNA作用表现出截然不同的结合行为, DNA对DTE衍生物具有明显的对映异构体选择性; DTE衍生物与DNA分子作用位点的选择性直接与构成位点的碱基对相关.

关键词: 分子动力学模拟, 手性药物, 二芳基乙烯衍生物, DNA, 旋转异构体, 结合模式

Abstract:

Binding modes between various DNA sequences and stereoisomeric rotamers of two dithienylethene derivatives(DTE1 and DTE2) representing photochromic switches were investigated in terms of molecular dynamics simulations and characterized by their binding energies. The result shows that minor groove binding(MiGB) is found to be the most robust binding mode between DNA and DTE(either DTE1 or DTE2). Due to steric hindrance, two DTE derivatives that are rotatable isomers exhibit distinct binding behaviors to DNA, and thus DNA has significant enantioselectivity for DTE derivatives. Moreover, the selectivity of the DTE derivative to the binding site of the DNA molecule is directly related to the base pair constitution, providing accurate theoretical guidance for precision medicine by chiral drugs based on this molecule.

Key words: Molecular dynamics, Chiral drug, Dithienylethene, DNA, Rotamer, Binding mode

中图分类号:

O641.3

TrendMD:

孙浩帆, 张凌怡, PATRICKNorman, 张维冰. 二芳基乙烯衍生物与DNA结合的分子动力学研究. 高等学校化学学报, 2019, 40(6): 1229.

SUN Haofan,ZHANG Lingyi,PATRICK Norman,ZHANG Weibing. Molecular Dynamic of Various DNA Sequences Binding of Dithienylethenes^†. Chem. J. Chinese Universities, 2019, 40(6): 1229.

图/表 9

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Conformation	Binding position
Conformation	MaGB	MaGI	MiGB	MiGI
P-DTE1	MaGB	MaGI	MiGB	MiGI
M-DTE1	MiGB	MaGI	MiGB	MiGI
P-DTE2	Bottom binding	MaGI	MiGB	MiGB
M-DTE2	MiGB	MaGI	MiGB	MiGB

Conformation	Binding position
Conformation	MaGB	MaGI	MiGB	MiGI
P-DTE1	MaGB	MaGI	MiGB	MiGI
M-DTE1	MiGB	MaGI	MiGB	MiGI
P-DTE2	Bottom binding	MaGI	MiGB	MiGB
M-DTE2	MiGB	MaGI	MiGB	MiGB

Conformation	Binding position
Conformation	MaGB	MaGI	MiGB	MiGI
P-DTE1	MiGB	MaGI	MiGB	MiGI
M-DTE1	MiGB	MaGI	MiGB	MiGI
P-DTE2	Bottom binding	MaGI	MiGB	MiGI
M-DTE2	Bottom binding	MaGI	MiGB	Bottom binding

Conformation	Binding position
Conformation	MaGB	MaGI	MiGB	MiGI
P-DTE1	MiGB	MaGI	MiGB	MiGI
M-DTE1	MiGB	MaGI	MiGB	MiGI
P-DTE2	Bottom binding	MaGI	MiGB	MiGI
M-DTE2	Bottom binding	MaGI	MiGB	Bottom binding

DNA	Conformation	Final position	E_coul/(kJ·mol^-1)	E_vdW/(kJ·mol^-1)
(6A-T +6C-G)×2	P-DTE1	No favorable binding	-259±75	-84±21
	M-DTE1	MiGB(A-T)	-828±71	-217±17
	P-DTE2	MiGB(between A-T and C-G)	-660±100	-113±21
	M-DTE2	MiGB(between A-T and C-G)	-598±88	-121±25