Molecular Dynamics Simulations and Steered Molecular Dynamics Simulations of Glabridin Bound to Wild Type and V30A Mutant Transthyretin: Ligand-linked Perturbation of Tertiary Conformation

doi:10.1007/s40242-018-8085-2

Abstract

Abstract: Transthyretin(TTR), as a tetrameric protein, functions as a neuroprotector. The native TTR homotetramer dissociates into dimers and monomers. Dimers and monomers self-assemble into amyloid fibrils, and this process can lead to some diseases. Native TTR homotetramer is a widely accepted model for TTR amyloid formation. In this study, simulations using molecular dynamics(MD) and steered MD(SMD) were performed to explore the mechanisms for glabridin(Glab), a specific inhibitor for TTR binding, for V30A mutant and wild-type(WT) TTR. MD simulation results indicate that, compared with Glab binding to WT and V30A mutant, the WT TTR could lead to the collapse of β-strands from Ser52 to His56 at chain A. This phenomenon facilitated the easy dissociation of chains A and C. Calculations of the binding free energy between the two chains showed that the V30A-Glab TTR complex displayed a lower binding energy than other systems(WT TTR and WT-Glab TTR). Then, SMD simulation was performed to explore the unbinding pathway for Glab through the WT and V30A mutant TTR. The results show that Lys15(chain A) produced a hydrogen bond with Glab at the force peak via the WT TTR tunnel. Meanwhile, in the V30A TTR mutant, the hydrogen bond between Lys15(chain A) and Glab was broken at the force peak. This condition was beneficial for Glab to be taken off from the protein. Our theoretical results will be useful in designing a new specific inhibitor of TTR protein to control the TTR homotetramer dissociation.

Key words: Transthyretin, Glabridin, Conformational change, Molecular mechanics-poisson Boltzmann surface area(MM-PBSA)

YU Zhengfei, HAN Jiarui, LIU Ye, ZHU Jingxuan, TIAN Xiaopian and HAN Weiwei. Molecular Dynamics Simulations and Steered Molecular Dynamics Simulations of Glabridin Bound to Wild Type and V30A Mutant Transthyretin: Ligand-linked Perturbation of Tertiary Conformation[J]. Chemical Research in Chinese Universities, 2018, 34(6): 995-1003.

References

[1] Verona G., Mangione P. P., Raimondi S., Giorgetti S., Faravelli G., Porcari R., Corazza A., Gillmore J. D., Hawkins P. N., Pepys M. B., Taylor G. W., Bellotti V., Sci. Rep., 2017, 7(1), 182
[2] Bulawa C. E., Connelly S., Devit M., Wang L., Weigel C., Fleming J. A., Packman J., Powers E. T., Wiseman R. L., Foss T. R., Wilson L. A., Kelly J. W., Labaudinière R., Proc. Natl. Acad. Sci. USA, 2012, 109(24), 9629
[3] Green N. S., Palaninathan S. K., Sacchettini J. C., Kelly J. W., J. Am. Chem. Soc., 2003, 125(44), 13404
[4] Cianci M., Folli C., Zonta P., Berni R., Zanotti G., Acta Crystallogr. D:Biol. Crystallogr., 2015, 71(18), 1582
[5] Coelho T., Merlini G., Fleming J. A., Judge D. P., Kelly J. W., Mau-rer M. S., Planté-Bordeneuve V., Labaudinière V., Mundayat R., Riley S., Lombardo I., Huertas P., Neurol. Ther., 2016, 5(1), 1
[6] Almeida M. R., Gales L., Damas A. M., Cardoso I., Saraiva M. J., Curr. Drug Targets CNS Neurol. Disord., 2005, 4(5), 587
[7] Ciccone L., Nencetti S., Rossello A., Stura E. A., Orlandini E., J. Enzyme Inhib. Med. Chem., 2016, 31(Suppl.1), 40
[8] Raya-Cruz M., Buades-Reines J., Gállego-Lezáun C., Ripoll-Vera T., Usón-Martín M., Cisneros-Barroso E., Med. Clin.(Barc.), 2017, 148(2), 63
[9] Hammarström P., Jiang X., Hurshman A. R., Powers E. T., Kelly J. W., Proc. Natl. Acad. Sci. USA, 2002, 99(Suppl.4), 16427
[10] Liu G., Ni W., Wang H., Li H., Zhang Y., Wang N., Wu Z., J. Peripher. Nerv. Syst., 2016, 22(1), 1911
[11] Penchala S. C., Connelly S., Wang Y., Park M. S., Zhao L., Baranczak A., Rappley I., Vogel H., Liedtke M., Witteles R. M., Powers E. T., Reixach N., Chan W. K., Wilson I. A., Kelly J. W., Graef I. A., Alhamadsheh M. M., Proc. Natl. Acad. Sci. USA, 2013, 110(24), 9992
[12] Coelho T., Maia L. F., Martins da Silva A., Waddington Cruz M., Planté-Bordeneuve V., Lozeron P., Suhr O. B., Campistol J. M., Conceição I. M., Schmidt H. H., Trigo P., Kelly J. W., Labaudinière R., Chan J., Packman J., Wilson A., Grogan D. R., Neurology, 2012, 79(8), 785
[13] Blake C. C., Geisow M. J., Oatley S. J., Rérat B., Rérat C., J. Mol. Biol., 1978, 121(3), 339
[14] Monaco H. L., Rizzi M., Coda A., Science, 1995, 268(5213), 1039
[15] Foss T. R., Wiseman R. L., Kelly J. W., Biochemistry, 2005, 44(47), 15525
[16] Adamski-Werner S. L., Palaninathan S. K., Sacchettini J. C., Kelly J. W., J. Med. Chem., 2004, 47(2), 355
[17] Waddington Cruz M., Amass L., Keohane D., Schwartz J., Li H., Gundapaneni B., Amyloid, 2016, 23(3), 178
[18] Kim B., Park H., Lee S. K., Park S. J., Koo T. S., Kang N. S., Hong K. B., Choi S., Eur. J. Med. Chem., 2016, 123, 777
[19] Hendrix A. S., Spoonmore T. J., Wilde A. D., Putnam N. E., Hammer N. D., Snyder D. J., Guelcher S. A., Skaar E. P., Cassat J. E., Antimicrob. Agents Chemother., 2016, 60(9), 5322
[20] Galant N. J., Bugyei-Twum A., Rakhit R., Walsh P., Sharpe S., Arslan P. E., Westermark P., Higaki J. N., Torres R., Tapia J., Chakrabartty A., Sci. Rep., 2016, 6, 25080
[21] You F., Li Q., Jin G., Zheng Y., Chen J., Yang H., BMC Neurosci., 2017, 18(1), 12
[22] Zhang N., Qi Y., Zhang H. J., Wang X., Li H., Shi Y., Guo Y. D., Front Plant Sci., 2016, 7, 1804
[23] Greene M. J., Klimtchuk E. S., Seldin D. C., Berk J. L., Connors L. H., Biochemistry, 2015, 54(2), 268
[24] Trivella D. B., dos Reis C. V., Lima L. M., Foguel D., Polikarpov I., J. Struct. Biol., 2012, 180(1),143
[25] Radovic B., Hussong R., Gerhäuser C., Meinl W., Frank N., Becker H., Köhrle J., Mol. Nutr. Food Res., 2010, 54(Suppl.2), 225
[26] Simmler C., Pauli G. F., Chen S. N., Fitoterapia, 2013, 90, 160
[27] Yokoyama T., Kosaka Y., Mizuguchi M., J. Med. Chem., 2014, 57(3), 1090
[28] Seino H., Arai Y., Nagao N., Ozawa N., Hamada K., PLoS One, 2016, 11(10), e0164061
[29] Kaczmarczyk-Sedlak I., Klasik-Ciszewska S., Wojnar W., Pharmacol. Rep., 2016, 68(5), 1036
[30] Wang W. P., Hul J., Sui H., Zhao Y. S., Feng J., Liu C., Pharmazie, 2016, 71(5), 252
[31] Zhang F., Hu C., Dong Y., Lin M. S., Liu J., Jiang X., Ge Y., Guo Y., Arch. Biochem. Biophys., 2013, 535(2), 120
[32] Zou L., Zhu J., Dong Y., Han W., Guo Y., Zhou H., RSC Adv., 2016, 6(99), 96816
[33] Biasini M., Bienert S., Waterhouse A., Arnold K., Studer G., Schmidt T., Kiefer F., Gallo Cassarino T., Bertoni M., Bordoli L., Schwede T., Nucleic Acids Res., 2014, 42, 252
[34] Abraham M. J., Gready J. E., J. Comput. Chem., 2011, 32(9), 2031
[35] Lin Z., van Gunsteren W. F., J. Comput. Chem., 2013, 34(32), 2796
[36] Kräutler V., van Gunsteren W. F., Hünenberger P. H., J. Comput. Chem., 2001, 22(5), 501
[37] Laino T., Hutter J., J. Chem. Phys., 2008, 129(7), 074102
[38] Jakobsen A. F., J. Chem. Phys., 2005, 122(12), 124901
[39] David C. C., Jacobs D. J., Methods Mol. Biol., 2014, 1084, 193
[40] Sittel F., Jain A., Stock G., J. Chem. Phys., 2014, 141(1), 014111
[41] Amadei A., Linssen A. B. M., Berendsen H. J. C., Proteins, 1993, 17, 412
[42] Phillips J. C., Braun R., Wang W., Gumbart J., Tajkhorshid E., Villa E., Chipot C., Skeel R. D., Kalé L., Schulten K., J. Comput. Chem., 2005, 26(16), 1781
[43] Darve E., Rodríguez-Gómez D., Pohorille A., J. Chem. Phys., 2008, 128(14), 144120
[44] Baker N. A., Sept D., Joseph S., Holst M. J., McCammon J. A., Nat. Acad. Sci. USA, 2001, 98(18), 10037
[45] Kumari R., Kumar R., Lynn A., J. Chem. Inf. Model., 2014, 54(7), 1951
[46] Wang J., Cieplak P., Kollman P. A., J. Comput. Chem., 2000, 21(19), 1049
[47] Wang J., Wolf R. M., Caldwell J. W., Kollman P. A., Case D. A., J. Comput. Chem., 2004, 25(9), 1157
[48] Kozlikova B., Sebestova E., Sustr V., Brezovsky J., Strnad O., Daniel L., Bednar D., Pavelka A., Manak M., Bezdeka M., Benes P., Kotry M., Gora A., Damborsky J., Sochor J., Bioinformatics, 2014, 30(18), 2684