Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis

Abstract Proteins are tiny players involved in the activation and deactivation of multiple signaling cascades through interactions in cells. The TNFR1 and MADD interact with each other and mediate downstream protein signaling pathways which cause neuronal cell death and Alzheimer’s disease. In the c...

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Autores principales:	Mubashir Hassan, Sara Zahid, Hany Alashwal, Andrzej Kloczkowski, Ahmed A. Moustafa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e70d2da2b797451bb7e608b7a173362c
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spelling	oai:doaj.org-article:e70d2da2b797451bb7e608b7a173362c2021-12-02T17:47:18ZMechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis10.1038/s41598-021-91606-42045-2322https://doaj.org/article/e70d2da2b797451bb7e608b7a173362c2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91606-4https://doaj.org/toc/2045-2322Abstract Proteins are tiny players involved in the activation and deactivation of multiple signaling cascades through interactions in cells. The TNFR1 and MADD interact with each other and mediate downstream protein signaling pathways which cause neuronal cell death and Alzheimer’s disease. In the current study, a molecular docking approach was employed to explore the interactive behavior of TNFR1 and MADD proteins and their role in the activation of downstream signaling pathways. The computational sequential and structural conformational results revealed that Asp400, Arg58, Arg59 were common residues of TNFR1 and MADD which are involved in the activation of downstream signaling pathways. Aspartic acid in negatively charged residues is involved in the biosynthesis of protein. However, arginine is a positively charged residue with the potential to interact with oppositely charged amino acids. Furthermore, our molecular dynamic simulation results also ensured the stability of the backbone of TNFR1 and MADD death domains (DDs) in binding interactions. This DDs interaction mediates some conformational changes in TNFR1 which leads to the activation of mediators proteins in the cellular signaling pathways. Taken together, a better understanding of TNFR1 and MADD receptors and their activated signaling cascade may help treat Alzheimer’s disease. The death domains of TNFR1 and MADD could be used as a novel pharmacological target for the treatment of Alzheimer’s disease by inhibiting the MAPK pathway.Mubashir HassanSara ZahidHany AlashwalAndrzej KloczkowskiAhmed A. MoustafaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mubashir Hassan Sara Zahid Hany Alashwal Andrzej Kloczkowski Ahmed A. Moustafa Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis
description	Abstract Proteins are tiny players involved in the activation and deactivation of multiple signaling cascades through interactions in cells. The TNFR1 and MADD interact with each other and mediate downstream protein signaling pathways which cause neuronal cell death and Alzheimer’s disease. In the current study, a molecular docking approach was employed to explore the interactive behavior of TNFR1 and MADD proteins and their role in the activation of downstream signaling pathways. The computational sequential and structural conformational results revealed that Asp400, Arg58, Arg59 were common residues of TNFR1 and MADD which are involved in the activation of downstream signaling pathways. Aspartic acid in negatively charged residues is involved in the biosynthesis of protein. However, arginine is a positively charged residue with the potential to interact with oppositely charged amino acids. Furthermore, our molecular dynamic simulation results also ensured the stability of the backbone of TNFR1 and MADD death domains (DDs) in binding interactions. This DDs interaction mediates some conformational changes in TNFR1 which leads to the activation of mediators proteins in the cellular signaling pathways. Taken together, a better understanding of TNFR1 and MADD receptors and their activated signaling cascade may help treat Alzheimer’s disease. The death domains of TNFR1 and MADD could be used as a novel pharmacological target for the treatment of Alzheimer’s disease by inhibiting the MAPK pathway.
format	article
author	Mubashir Hassan Sara Zahid Hany Alashwal Andrzej Kloczkowski Ahmed A. Moustafa
author_facet	Mubashir Hassan Sara Zahid Hany Alashwal Andrzej Kloczkowski Ahmed A. Moustafa
author_sort	Mubashir Hassan
title	Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis
title_short	Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis
title_full	Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis
title_fullStr	Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis
title_full_unstemmed	Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis
title_sort	mechanistic insights into tnfr1/madd death domains in alzheimer’s disease through conformational molecular dynamic analysis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e70d2da2b797451bb7e608b7a173362c
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Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis

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