A comparative study of trypsin specificity based on QM/MM molecular dynamics simulation and QM/MM GBSA calculation

doi:10.1080/07391102.2014.1003146

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	A comparative study of trypsin specificity based on QM/MM molecular dynamics simulation and QM/MM GBSA calculation
	Chen, Jianzhong 2; Wang, Jinan 1; Zhang, Qinggang 3; Chen, Kaixian1 ; Zhu, Weiliang1
刊名	JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
	2015-12-02
卷号	33 期号:12 页码:2606-2618
关键词	QM MM molecular dynamics simulations MM-GBSA method trypsin specificity semi-empirical Hamiltonian binding free energies
ISSN号	0739-1102
DOI	10.1080/07391102.2014.1003146
文献子类	Article
英文摘要	Hydrogen bonding and polar interactions play a key role in identification of protein-inhibitor binding specificity. Quantum mechanics/molecular mechanics molecular dynamics (QM/MM MD) simulations combined with DFT and semi-empirical Hamiltonian (AM1d, RM1, PM3, and PM6) methods were performed to study the hydrogen bonding and polar interactions of two inhibitors BEN and BEN1 with trypsin. The results show that the accuracy of treating the hydrogen bonding and polar interactions using QM/MM MD simulation of PM6 can reach the one obtained by the DFT QM/MM MD simulation. Quantum mechanics/molecular mechanics generalized Born surface area (QM/MM-GBSA) method was applied to calculate binding affinities of inhibitors to trypsin and the results suggest that the accuracy of binding affinity prediction can be significantly affected by the accurate treatment of the hydrogen bonding and polar interactions. In addition, the calculated results also reveal the binding specificity of trypsin: (1) the amidinium groups of two inhibitors generate favorable salt bridge interaction with Asp189 and form hydrogen bonding interactions with Ser190 and Gly214, (2) the phenyl of inhibitors can produce favorable van der Waals interactions with the residues His58, Cys191, Gln192, Trp211, Gly212, and Cys215. This systematic and comparative study can provide guidance for the choice of QM/MM MD methods and the designs of new potent inhibitors targeting trypsin.
资助项目	National Natural Science Foundation of China[11274206] ; National Natural Science Foundation of China[81273435] ; National Natural Science Foundation of China[21403283] ; Shandong province university science and technology project[J14LJ07] ; Dr. Start-up Foundation of Shandong Jiaotong University[00000000] ; Postdoctoral Science Foundation of China[2014M560362]
WOS关键词	BINDING FREE-ENERGIES ; PARTICLE MESH EWALD ; SEMIEMPIRICAL METHODS ; CHEMICAL-SHIFTS ; HYDROGEN-BONDS ; HIV-1 PROTEASE ; PK(A) VALUES ; FORCE-FIELD ; SIDE-CHAIN ; LIGAND
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics
语种	英语
出版者	TAYLOR & FRANCIS INC
WOS记录号	WOS:000367811300007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276291]
专题	药物发现与设计中心
通讯作者	Chen, Jianzhong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Discovery & Design Ctr, Shanghai 201203, Peoples R China; 2.Shandong Jiaotong Univ, Sch Sci, Jinan 250014, Peoples R China; 3.Shandong Normal Univ, Coll Phys & Elect, Jinan 250014, Peoples R China
推荐引用方式 GB/T 7714	Chen, Jianzhong,Wang, Jinan,Zhang, Qinggang,et al. A comparative study of trypsin specificity based on QM/MM molecular dynamics simulation and QM/MM GBSA calculation[J]. JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS,2015,33(12):2606-2618.
APA	Chen, Jianzhong,Wang, Jinan,Zhang, Qinggang,Chen, Kaixian,&Zhu, Weiliang.(2015).A comparative study of trypsin specificity based on QM/MM molecular dynamics simulation and QM/MM GBSA calculation.JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS,33(12),2606-2618.
MLA	Chen, Jianzhong,et al."A comparative study of trypsin specificity based on QM/MM molecular dynamics simulation and QM/MM GBSA calculation".JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS 33.12(2015):2606-2618.