Prediksi Stabilitas Mucroporin sebagai Kandidat Obat Berbasis Peptida melalui Simulasi Dinamika Molekular

Taufik Muhammad Fakih, Mentari Luthfika Dewi, Eky Syahroni

Abstrak


Beberapa peptida yang terkandung dalam racun kalajengking (Lychas mucronatus) menunjukkan beragam aktivitas biologis dengan spesifisitas tinggi terhadap target. Peptida ini memiliki efek potensial terhadap mikroba dan menunjukkan potensi untuk memodulasi berbagai mekanisme biologis yang terlibat dalam imunitas, saraf, kardiovaskular, dan penyakit neoplastik. Keragaman struktural dan fungsional yang penting dari peptida tersebut membuktikan bahwa peptida dari racun kalajengking dapat digunakan dalam pengembangan obat spesifik baru. Melalui penelitian ini akan dilakukan identifikasi, evaluasi, dan eksplorasi terhadap stabilitas peptida Mucroporin yang diproduksi dari racun kalajengking dengan menggunakan simulasi dinamika molekular. Sekuens molekul peptida Mucroporin dimodelkan dengan menggunakan server PEPstrMOD. Konformasi terbaik hasil pemodelan dipilih untuk diamati stabilitasnya dengan menggunakan software Gromacs 2016.3. Trajektori yang terbentuk kemudian dianalisis berdasarkan visulasiasi dengan menggunakan software VMD 1.9.4 serta dilakukan analisis grafik RMSD dan RMSF. Hasil analisis trajektori dari simulasi dinamika molekular membuktikan bahwa molekul peptida Mucroporin-S2 memiliki stabilitas yang paling baik. Dengan demikian, molekul peptida tersebut diprediksi dapat dipilih sebagai kandidat obat berbasis peptida.

Kata Kunci


racun kalajengking (Lychas mucronatus); molekul peptida Mucroporin; simulasi dinamika molekular; studi in silico

Teks Lengkap:

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Referensi


. Li K, Chung-Davidson YW, Bussy U, Li W. Recent advances and applications of experimental technologies in marine natural product research. Marine Drugs. 2015;13(5):2694-2713. https://doi.org/10.3390/md13052694

. Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. Journal of Natural Products. 2007;70(3):461-477. https://doi.org/10.1021/np068054v

. Clardy J, Walsh C. Lessons from natural molecules. Nature. 2004;432(7019):829-837. https://doi.org/10.1038/nature03194

. Yuan H, Ma Q, Ye L, Piao G. The traditional medicine and modern medicine from natural products. Molecules. 2016;21(5):559. https://doi.org/10.3390/molecules21050559

. Pennington MW, Czerwinski A, Norton RS. Peptide therapeutics from venom: Current status and potential. Bioorganic Med Chem. 2018;26(10):2738-2758. https://doi.org/10.1016/j.bmc.2017.09.029

. Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, et al. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnology Advances. 2015;33(8):1582-1614. https://doi.org/10.1016/j.biotechadv.2015.08.001

. Cragg GM, Newman DJ. Natural products: A continuing source of novel drug leads. Biochimica et Biophysica Acta - General Subjects. 2013;1830(6):3670-3695. https://doi.org/10.1016/j.bbagen.2013.02.008

. Bergeron ZL, Bingham JP. Scorpion toxins specific for potassium (K+) channels: A historical overview of peptide bioengineering. Toxins. 2012;4(11):1082-1119. https://doi.org/10.3390/toxins4111082

. Oukkache N, El Jaoudi R, Ghalim N, Chgoury F, Bouhaouala B, El Mdaghri N, et al. Evaluation of the lethal potency of scorpion and snake venoms and comparison between intraperitoneal and intravenous injection routes. Toxins (Basel). 2014;6(6):1873-1881. https://doi.org/10.3390/toxins6061873

. Rodríguez De La Vega RC, Possani LD. Current views on scorpion toxins specific for K+-channels. Toxicon. 2004;43(8):865-875. https://doi.org/10.1016/j.toxicon.2004.03.022

. Ortiz E, Gurrola GB, Schwartz EF, Possani LD. Scorpion venom components as potential candidates for drug development. Toxicon. 2015;93:125-135. https://doi.org/10.1016/j.toxicon.2014.11.233

. Bawaskar HS. Can scorpions be useful? Lancet. 2007;370(9599):1664. https://doi.org/10.1016/S0140-6736(07)61688-2

. Touchard A, Aili SR, Fox EGP, Escoubas P, Orivel J, Nicholson GM, et al. The biochemical toxin arsenal from ant venoms. Toxins. 2016;8(1):30. https://doi.org/10.3390/toxins8010030

. Zhijian C, Feng L, Yingliang W, Xin M, Wenxin L. Genetic mechanisms of scorpion venom peptide diversification. Toxicon. 2006;47(3):348-855. https://doi.org/10.1016/j.toxicon.2005.11.013

. Almaaytah A, Albalas Q. Scorpion venom peptides with no disulfide bridges: A review. Peptides. 2014;51:35-45. https://doi.org/10.1016/j.peptides.2013.10.021

. De Melo ET, Estrela AB, Santos ECG, Machado PRL, Farias KJS, Torres TM, et al. Structural characterization of a novel peptide with antimicrobial activity from the venom gland of the scorpion Tityus stigmurus: Stigmurin. Peptides. 2015;68:3-10. https://doi.org/10.1016/j.peptides.2015.03.003

. Ortiz E, Possani LD. The unfulfilled promises of scorpion insectotoxins. Journal of Venomous Animals and Toxins Including Tropical Diseases. 2015; 21:16. https://doi.org/10.1186/s40409-015-0019-6

. Rowe AH, Xiao Y, Rowe MP, Cummins TR, Zakon HH. Voltage-gated sodium channel in grasshopper mice defends against bark scorpion toxin. Science (80- ). 2013;342(6157):441-446. https://doi.org/10.1126/science.1236451

. Domingues TM, Perez KR, Riske KA. Revealing the Mode of Action of Halictine Antimicrobial Peptides: A Comprehensive Study with Model Membranes. Langmuir. 2020;36(19):5145-5155. https://doi.org/10.1021/acs.langmuir.0c00282

. Dai C, Ma Y, Zhao Z, Zhao R, Wang Q, Wu Y, et al. Mucroporin, the first cationic host defense peptide from the venom of Lychas mucronatus. Antimicrob Agents Chemother. 2008;52(11):3967-3972. https://doi.org/10.1128/AAC.00542-08

. Li Q, Zhao Z, Zhou D, Chen Y, Hong W, Cao L, et al. Virucidal activity of a scorpion venom peptide variant mucroporin-M1 against measles, SARS-CoV and influenza H5N1 viruses. Peptides. 2011;32(7):1518-1525. https://doi.org/10.1016/j.peptides.2011.05.015

. Zhao Z, Hong W, Zeng Z, Wu Y, Hu K, Tian X, et al. Mucroporin-M1 inhibits hepatitis B virus replication by activating the mitogen-activated protein kinase (MAPK) pathway and down-regulating HNF4α in vitro and in vivo. J Biol Chem. 2012;287(36):30181-30190. https://doi.org/10.1074/jbc.M112.370312

. Zeng Z, Zhang Q, Hong W, Xie Y, Liu Y, Li W, et al. A Scorpion Defensin BmKDfsin4 Inhibits Hepatitis B Virus Replication in Vitro. Toxins. 2016;8(5):124. https://doi.org/10.3390/toxins8050124

. Yan R, Zhao Z, He Y, Wu L, Cai D, Hong W, et al. A new natural α-helical peptide from the venom of the scorpion Heterometrus petersii kills HCV. Peptides. 2011;32(1):11-19. https://doi.org/10.1016/j.peptides.2010.10.008

. Shenker S, O’Donnell CW, Devadas S, Berger B, Waldispühl J. Efficient traversal of beta-sheet protein folding pathways using ensemble models. J Comput Biol. 2011;18(11):1635-1647. https://doi.org/10.1089/cmb.2011.0176

. Georgoulia PS, Glykos NM. On the foldability of tryptophan-containing tetra-and pentapeptides: An exhaustive molecular dynamics study. J Phys Chem B. 2013;117(18):5522-5532. https://doi.org/10.1021/jp401239v

. Ho BK, Dill KA. Folding very short peptides using molecular dynamics. PLoS Comput Biol. 2006;2(4):e27. https://doi.org/10.1371/journal.pcbi.0020027

. Mustafa S, Balkhy H, Gabere M. Peptide-Protein Interaction Studies of Antimicrobial Peptides Targeting Middle East Respiratory Syndrome Coronavirus Spike Protein: An In Silico Approach. Adv Bioinformatics. 2019;6815105. https://doi.org/10.1155/2019/6815105

. Hmed B, Serria HT, Mounir ZK. Scorpion peptides: Potential use for new drug development. Journal of Toxicology. 2013;958797. https://doi.org/10.1155/2013/958797

. Vilas Boas LCP, Campos ML, Berlanda RLA, de Carvalho Neves N, Franco OL. Antiviral peptides as promising therapeutic drugs. Cellular and Molecular Life Sciences. 2019;76(18):3525-3542. https://doi.org/10.1007/s00018-019-03138-w

. Singh S, Singh H, Tuknait A, Chaudhary K, Singh B, Kumaran S, et al. PEPstrMOD: Structure prediction of peptides containing natural, non-natural and modified residues. Biol Direct. 2015;10:73. https://doi.org/10.1186/s13062-015-0103-4

. Harpreet Kaur, Aarti Garg, G.P.S. Raghava. PEPstr: A de novo Method for Tertiary Structure Prediction of Small Bioactive Peptides. Protein Pept Lett. 2007;14(7):626-631. https://doi.org/10.2174/092986607781483859

. Aragones JL, Noya EG, Valeriani C, Vega C. Free energy calculations for molecular solids using GROMACS. J Chem Phys. 2013;139:034104. https://doi.org/10.1063/1.4812362

. Pronk S, Páll S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, et al. GROMACS 4.5: A high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics. 2013;29(7):845-854. https://doi.org/10.1093/bioinformatics/btt055

. Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, et al. Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1-2:19-25. https://doi.org/10.1016/j.softx.2015.06.001

. Makarewicz T, Kaźmierkiewicz R. Molecular dynamics simulation by GROMACS using GUI plugin for PyMOL. J Chem Inf Model. 2013;53(5):1229-1234. https://doi.org/10.1021/ci400071x

. van der Spoel D, van Maaren PJ, Caleman C. GROMACS molecule & liquid database. Bioinformatics. 2012;28(5):752-753. https://doi.org/10.1093/bioinformatics/bts020

. Petrov D, Zagrovic B. Are Current Atomistic Force Fields Accurate Enough to Study Proteins in Crowded Environments? PLoS Comput Biol. 2014;10(5):e1003638. https://doi.org/10.1371/journal.pcbi.1003638

. Serafeim AP, Salamanos G, Patapati KK, Glykos NM. Sensitivity of Folding Molecular Dynamics Simulations to even Minor Force Field Changes. J Chem Inf Model. 2016;56(10):2035-2041. https://doi.org/10.1021/acs.jcim.6b00493

. Wang H, Gao X, Fang J. Multiple Staggered Mesh Ewald: Boosting the Accuracy of the Smooth Particle Mesh Ewald Method. J Chem Theory Comput. 2016;12(11):5596-5608. https://doi.org/10.1021/acs.jctc.6b00701

. Humphrey W, Dalke A, Schulten K. VMD: Visual molecular dynamics. J Mol Graph. 1996;14(1):33-38. https://doi.org/10.1016/0263-7855(96)00018-5

. Sargsyan K, Grauffel C, Lim C. How Molecular Size Impacts RMSD Applications in Molecular Dynamics Simulations. J Chem Theory Comput. 2017;13(4):1518-1524. https://doi.org/10.1021/acs.jctc.7b00028

. Junaid M, Muhseen ZT, Ullah A, Wadood A, Liu J, Zhang H. Molecular modeling and molecular dynamics simulation study of the human Rab9 and RhoBTB3 C-terminus complex. Bioinformation. 2014;12(2):e0170822. https://doi.org/10.6026/97320630010757

. Chakraborty S, Zheng W. Decrypting the structural, dynamic, and energetic basis of a monomeric kinesin interacting with a tubulin dimer in three ATPase states by all-atom molecular dynamics simulation. Biochemistry. 2015;54(3):859-869. https://doi.org/10.1021/bi501056h




DOI: https://doi.org/10.25077/jsfk.7.3.210-217.2020

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