Identification of possible siRNA molecules for TDP43 mutants causing amyotrophic lateral sclerosis: In silico design and molecular dynamics study |
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| Affiliation: | 1. Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;2. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;3. Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;4. Center for Interventional Oncology, National Cancer Institute & Clinical Center, National Institutes of Health, Bethesda, MD;1. Department of Mathematics and Statistics, International Islamic University, Islamabad 44000, Pakistan;2. Department of Mathematics, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan;2. Department of Diagnostic Imaging, University Campus Bio-Medico of Rome, Rome, Italy;2. Fraunhofer Institute of Optronics, System Technologies and Image Exploitation IOSB, Karlsruhe, Germany;3. Steinbeis-Transfer-Institut Klinische Hämatoonkologie, Donauwörth, Germany |
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| Abstract: | The DNA binding protein, TDP43 is a major protein involved in amyotrophic lateral sclerosis and other neurological disorders such as frontotemporal dementia, Alzheimer disease, etc. In the present study, we have designed possible siRNAs for the glycine rich region of tardbp mutants causing ALS disorder based on a systematic theoretical approach including (i) identification of respective codons for all mutants (reported at the protein level) based on both minimum free energy and probabilistic approaches, (ii) rational design of siRNA, (iii) secondary structure analysis for the target accessibility of siRNA, (iii) determination of the ability of siRNA to interact with mRNA and the formation/stability of duplex via molecular dynamics study for a period of 15 ns and (iv) characterization of mRNA–siRNA duplex stability based on thermo-physical analysis. The stable GC-rich siRNA expressed strong binding affinity towards mRNA and forms stable duplex in A-form. The linear dependence between the thermo-physical parameters such as Tm, GC content and binding free energy revealed the ability of the identified siRNAs to interact with mRNA in comparable to that of the experimentally reported siRNAs. Hence, this present study proposes few siRNAs as the possible gene silencing agents in RNAi therapy based on the in silico approach. |
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| Keywords: | siRNA Amyotrophic lateral sclerosis RNAi Molecular dynamics simulation |
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