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Molecular modeling to investigate the binding of Congo red toward GNNQQNY protofibril and in silico virtual screening for the identification of new aggregation inhibitors

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Abstract

Understanding the nature of the recognition between amyloid protofibrils and dye molecules at the molecular level is essential to improving instructive guides for designing novel molecular probes or new inhibitors. However, the atomic details of the binding between dyes and amyloid fibrils are still not fully understood. In this study, molecular docking, consensus scoring, molecular dynamics (MD), and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analyses were integrated to investigate the binding between Congo red (CR) and the GNNQQNY protofibril from yeast prion protein Sup35 and to further evaluate their binding stabilities and affinities. Our results reveal that there are four CR binding sites located on GNNQQNY protofibril surface. These four CR binding sites adopt dual binding modes by which CR binding with its long axis parallel and perpendicular to the long axis of the protofibril. In addition, CR was also found to bind to the edge of the protofibril via hydrophobic/aromatic and hydrogen-bonding interactions, which is inferred as the possible inhibition mechanism to prevent the elongation of the protofibril from the addition of incoming peptides. Virtual screening from National Cancer Institute (NCI) database obtained three hit compounds with higher binding affinity than CR to the edge of the protofibril due to the fact that the central parts of these compounds are able to form additional hydrogen bonds with the protofibril. The results of the study could be useful for the development of new molecular probes or inhibitors for clinical applications.

Investigation of the Congo red binding toward GNNQQNY protofibril and in silico virtual screening for the identification of new aggregation inhibitors

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Acknowledgments

The authors gratefully acknowledge the financial supports from Atomic Energy Council of Taiwan (Project number: ARA010203), National Science Council of Taiwan (Project numbers: 99-2221-E-027-022-MY3, 99-2221-E-027-037-MY2, and 99-2622-E-027-003-CC3), the Institute of Nuclear Energy Research of Taiwan (Project number: 1002001INER081), and National Taipei University of Technology and Taipei Medical University (Project number: NTUT-TMU-100-09).

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Authors and Affiliations

  1. Chemistry Division, Institute of Nuclear Energy Research, 1000, Wunhua Rd., Longtan Township, Taoyuan County, 32546, Taiwan

    Jian-Hua Zhao, Wei-Hsi Chen & Lee-Chung Men

  2. Graduate Institute of Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd., Taipei, 10608, Taiwan

    Hsuan-Liang Liu & Pavadai Elumalai

  3. Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd., Taipei, 10608, Taiwan

    Hsuan-Liang Liu

  4. Everlight Chemical Industrial Corporation, 6th Fl, 77, Tun Hua South Road, Sec.2, Taipei, 106, Taiwan

    Kung-Tien Liu

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  1. Jian-Hua Zhao
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  4. Wei-Hsi Chen
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Correspondence to Hsuan-Liang Liu or Wei-Hsi Chen.

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Zhao, JH., Liu, HL., Elumalai, P. et al. Molecular modeling to investigate the binding of Congo red toward GNNQQNY protofibril and in silico virtual screening for the identification of new aggregation inhibitors. J Mol Model 19, 151–162 (2013). https://doi.org/10.1007/s00894-012-1532-y

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  • DOI: https://doi.org/10.1007/s00894-012-1532-y

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