Using steered molecular dynamics to study the interaction between ADP and the nucleotide-binding domain of yeast Hsp70 protein Ssa1
Using steered molecular dynamics to study the interaction between ADP and the nucleotide-binding domain of yeast Hsp70 protein Ssa1
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利用引导分子动力学研究 ADP 与酵母 Hsp70 蛋白 Ssa1 核苷酸结合域之间的相互作用
DOI：
10.1007/s10822-018-0136-8
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发表时间：
2018-11
影响因子：
3.5
通讯作者：
Youtao Song
中科院分区：
文献类型：
--
作者：
YouLin Xue;Qiaoshi Zhang;Yuna Sun;Xiaohong Zhou;Ian P. Hurley;Gary W. Jones;Youtao Song
遗传学实验已经鉴定了位于Ssa 1的亚结构域IA中的六个突变（A17 V、R23 H、G32 D、G32 S、R34 K、V372 I），其影响酵母[PSI+]朊病毒的繁殖。然而，这些突变的基本分子机制仍不清楚。六个突变位点存在于核苷酸结合结构域（NBD）的IA亚结构域中。ATP酶亚结构域IA是Hsp70分子伴侣结构域间变构的重要介导者，其突变和改变可能影响底物结合结构域的功能。此外，ADP释放是ATP酶循环的限速步骤，ATP酶循环的失调影响酵母[PSI+]朊病毒的繁殖。在这项工作中，操纵分子动力学（SMD）模拟进行探索ADP和NBD之间的相互作用。结果表明，在SMD模拟过程中，疏水相互作用是占主导地位的突变体内的ADP的结合状态的变化是一个潜在的原因在体内酵母[PSI+]朊病毒繁殖的影响。此外，我们确定的主要残基的ATP酶结构域中，直接构成主要的疏水相互作用网络，并直接影响ADP的相互作用状态与NBD的Ssa1。此外，这种计算机分析重申了先前实验确定的在ADP结合中涉及的Hsp70 ATP酶结构域中的残基的重要性，并且还鉴定了可能涉及该过程的新残基。
Genetics experiments have identified six mutations located in the subdomain IA (A17V, R23H, G32D, G32S, R34K, V372I) of Ssa1 that influence propagation of the yeast [PSI+] prion. However, the underlining molecular mechanisms of these mutations are still unclear. The six mutation sites are present in the IA subdomain of the nucleotide-binding domain (NBD). The ATPase subdomain IA is a critical mediator of inter-domain allostery in Hsp70 molecular chaperones, so the mutation and changes in this subdomain may influence the function of the substrate-binding domain. In addition, ADP release is a rate-limiting step of the ATPase cycle and dysregulation of the ATPase cycle influences the propagation of the yeast [PSI+] prion. In this work, steered molecular dynamics (SMD) simulations were performed to explore the interaction between ADP and NBD. Results suggest that during the SMD simulations, hydrophobic interactions are predominant and variations in the binding state of ADP within the mutants is a potential reason for in vivo effects on yeast [PSI+] prion propagation. Additionally, we identify the primary residues in the ATPase domain that directly constitute the main hydrophobic interaction network and directly influence the ADP interaction state with the NBD of Ssa1. Furthermore, this in silico analysis reaffirms the importance of previously experimentally-determined residues in the Hsp70 ATPase domain involved in ADP binding and also identifies new residues potentially involved in this process.
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影响因子：
5.6
作者：
Bhattacharya, Akash;Kurochkin, Alexander V.;Yip, Grover N. B.;Zhang, Yongbo;Bertelsen, Eric B.;Zuiderweg, Erik R. P.
通讯作者：
Zuiderweg, Erik R. P.
影响因子：
5.8
作者：
Pronk, Sander;Pall, Szilard;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
8
作者：
Arakawa, Akihiko;Handa, Noriko;Yokoyama, Shigeyuki
通讯作者：
Yokoyama, Shigeyuki
DOI：
10.4172/0974-276x.s1.064
发表时间：
2013-06
期刊：
--
影响因子：
--
作者：
E. A. Cavalheiro
通讯作者：
E. A. Cavalheiro
DOI：
10.1007/s00249-010-0638-3
发表时间：
2011-02-01
影响因子：
2
作者：
Kalikka, Janne;Akola, Jaakko
通讯作者：
Akola, Jaakko