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Using steered molecular dynamics to study the interaction between ADP and the nucleotide-binding domain of yeast Hsp70 protein Ssa1

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Abstract

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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Acknowledgements

The whole study was supported by the National Natural Science Foundation of China (31570154 and 31201285), the China Postdoctoral Science Foundation (2017M611752), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry of China (2013693), the Serving Local Project of the Education Department of Liaoning Province, China (LFW201704) and the Grants for Distinguished Professors of Liaoning Province.

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Authors and Affiliations

  1. School of Environmental Science, College of Environment, Liaoning University, No. 66 Chongshan Middle Road, Huanggu District, Shenyang, 110036, Liaoning, China

    You-Lin Xue, Qiaoshi Zhang, Yuna Sun, Xiaohong Zhou & Youtao Song

  2. College of Light Industry, Liaoning University, Shenyang, 110036, China

    You-Lin Xue

  3. Centre for Biomedical Science Research, School of Clinical and Applied Sciences, Faculty of Health and Social Sciences, Leeds Beckett University, Leeds, LS13HE, UK

    Ian P. Hurley & Gary W. Jones

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  1. You-Lin Xue
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  2. Qiaoshi Zhang
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  3. Yuna Sun
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  4. Xiaohong Zhou
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  7. Youtao Song
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Correspondence to Youtao Song.

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Xue, YL., Zhang, Q., Sun, Y. et al. Using steered molecular dynamics to study the interaction between ADP and the nucleotide-binding domain of yeast Hsp70 protein Ssa1. J Comput Aided Mol Des 32, 1217–1227 (2018). https://doi.org/10.1007/s10822-018-0136-8

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  • DOI: https://doi.org/10.1007/s10822-018-0136-8

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