Molecular Dynamics Simulations Revealed the Regulation of Ligands to the Interactions between Androgen Receptor and Its Coactivator

doi:10.1021/acs.jcim.8b00283

	Molecular Dynamics Simulations Revealed the Regulation of Ligands to the Interactions between Androgen Receptor and Its Coactivator
	Liu, Na 1,2; Zhou, Wenfang 3; Guo, Yue 1,2; Wang, Junmei 4; Fu, Weitao 3; Sun, Huiyong 3; Liu, Dan 3; Duan, Mojie 1; Hou, Tingjun 3
刊名	JOURNAL OF CHEMICAL INFORMATION AND MODELING
	2018-08-01
卷号	58 期号:8 页码:1652-1661
ISSN号	1549-9596
DOI	10.1021/acs.jcim.8b00283
英文摘要	The androgen receptor (AR) plays important Agonist binding roles in gene expression regulation, sexual phenotype maintenance, and prostate cancer (PCa) development. The communications between the AR ligand-binding domain (LBD) and its coactivator are critical to the activation of AR. It is still unclear how the ligand binding would affect the AR coactivator interactions. In this work, the effects of the ligand binding on the AR coactivator communications were explored by molecular dynamics (MD) simulations. The results showed that the ligand binding regulates the residue interactions in the function site AF-2. The ligand-to-coactivator allosteric pathway, which involves the coactivator, helix 3 (H3), helix 4 (H4), the loop between H3 and H4 (L3), and helix 12 (H12), and ligands, was characterized. In addition, the interactions of residues on the function site BF-3, especially on the boundary of AF-2 and BF-3, are also affected by the ligands. The MM/GBSA free energy calculations demonstrated that the binding affinity between the coactivator and apo-AR is roughly weaker than those between the coactivator and antagonistic ARs but stronger than those between the coactivator and agonistic ARs. The results indicated that the long-range electrostatic interactions and the conformational entropies are the main factors affecting the binding free energies. In addition, the F876L mutation on AR-LBD affects the ligand-to-coactivator allosteric pathway, which could be the reason for point mutation induced tolerance for the antagonistic drugs such as enzalutamide. Our study would help to develop novel drug candidates against PCa.
资助项目	National Major Basic Research Program of China[2016YFA0501701] ; National Major Basic Research Program of China[2016YFB0201700] ; National Science Foundation of China[21773298] ; National Science Foundation of China[21403291] ; National Science Foundation of China[21575128] ; National Science Foundation of China[81603031] ; National Institutes of Health of USA[R01-GM079383] ; National Institutes of Health of USA[R21-GM097617]
WOS关键词	ADVANCED PROSTATE-CANCER ; BINDING DOMAIN ; RESISTANCE MECHANISMS ; NUCLEAR RECEPTORS ; GENERALIZED BORN ; FORCE-FIELD ; PROTEIN ; ENZALUTAMIDE ; DISCOVERY ; SURFACE
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Computer Science
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000443526000016
资助机构	National Major Basic Research Program of China ; National Major Basic Research Program of China ; National Science Foundation of China ; National Science Foundation of China ; National Institutes of Health of USA ; National Institutes of Health of USA ; National Major Basic Research Program of China ; National Major Basic Research Program of China ; National Science Foundation of China ; National Science Foundation of China ; National Institutes of Health of USA ; National Institutes of Health of USA ; National Major Basic Research Program of China ; National Major Basic Research Program of China ; National Science Foundation of China ; National Science Foundation of China ; National Institutes of Health of USA ; National Institutes of Health of USA ; National Major Basic Research Program of China ; National Major Basic Research Program of China ; National Science Foundation of China ; National Science Foundation of China ; National Institutes of Health of USA ; National Institutes of Health of USA
内容类型	期刊论文
源URL	[http://ir.wipm.ac.cn/handle/112942/13076]
专题	中国科学院武汉物理与数学研究所
通讯作者	Duan, Mojie; Hou, Tingjun
作者单位	1.Chinese Acad Sci, Wuhan Inst Phys & Math, State Key Lab Magnet Resonance & Atom & Mol Phys, Natl Ctr Magnet Resonance Wuhan,Key Lab Magnet Re, Wuhan 430071, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China 4.Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA
推荐引用方式 GB/T 7714	Liu, Na,Zhou, Wenfang,Guo, Yue,et al. Molecular Dynamics Simulations Revealed the Regulation of Ligands to the Interactions between Androgen Receptor and Its Coactivator[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2018,58(8):1652-1661.
APA	Liu, Na.,Zhou, Wenfang.,Guo, Yue.,Wang, Junmei.,Fu, Weitao.,...&Hou, Tingjun.(2018).Molecular Dynamics Simulations Revealed the Regulation of Ligands to the Interactions between Androgen Receptor and Its Coactivator.JOURNAL OF CHEMICAL INFORMATION AND MODELING,58(8),1652-1661.
MLA	Liu, Na,et al."Molecular Dynamics Simulations Revealed the Regulation of Ligands to the Interactions between Androgen Receptor and Its Coactivator".JOURNAL OF CHEMICAL INFORMATION AND MODELING 58.8(2018):1652-1661.