Structure based computational RNA design towards MafA transcriptional repressor implicated in multiple myeloma.

Autor: Yıldırım Akdeniz G; Department of Molecular Biology, Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Sabancı University, 34956, Tuzla, İstanbul, Turkey. Electronic address: gunes.yildirim@sabanciuniv.edu., Timuçin AC; Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acıbadem Mehmet Ali Aydınlar University, 34752, Ataşehir, İstanbul, Turkey. Electronic address: ahmet.timucin@acibadem.edu.tr.
Jazyk: angličtina
Zdroj: Journal of molecular graphics & modelling [J Mol Graph Model] 2024 Nov; Vol. 132, pp. 108839. Date of Electronic Publication: 2024 Jul 31.
DOI: 10.1016/j.jmgm.2024.108839
Abstrakt: Multiple myeloma is recognized as the second most common hematological cancer. MafA transcriptional repressor is an established mediator of myelomagenesis. While there are multitude of drugs available for targeting various effectors in multiple myeloma, current literature lacks a candidate RNA based MafA modulator. Thus, using the structure of MafA homodimer-consensus target DNA, a computational effort was implemented to design a novel RNA based chemical modulator against MafA. First, available MafA-consensus DNA structure was employed to generate an RNA library. This library was further subjected to global docking to select the most plausible RNA candidates, preferring to bind DNA binding region of MafA. Following global docking, MD-ready complexes that were prepared via local docking program, were subjected to 500 ns of MD simulations. First, each of these MD simulations were analyzed for relative binding free energy through MM-PBSA method, which pointed towards a strong RNA based MafA binder, RNA1. Second, through a detailed MD analysis, RNA1 was shown to prefer binding to a single monomer of the dimeric DNA binding domain of MafA using higher number of hydrophobic interactions compared with positive control MafA-DNA complex. At the final phase, a principal component analyses was conducted, which led us to identify the actual interaction region of RNA1 and MafA monomer. Overall, to our knowledge, this is the first computational study that presents an RNA molecule capable of potentially targeting MafA protein. Furthermore, limitations of our study together with possible future implications of RNA1 in multiple myeloma were also discussed.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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