Understanding the self-assembly dynamics of A/T absent 'four-way DNA junctions with sticky ends' at altered physiological conditions through molecular dynamics simulations.

Elucidation of structure and dynamics of alternative higher-order structures of DNA such as in branched form could be targeted for therapeutics designing. Herein, we are reporting the intrinsically dynamic and folds transitions of an unusual DNA junction with sequence d(CGGCGGCCGC)4 which self-assembles into a four-way DNA junction form with sticky ends using long interval molecular simulations under various artificial physiological conditions. The original crystal structure coordinates (PDB ID: 3Q5C) for the selected DNA junction was considered for a total of 1.1 µs molecular dynamics simulation interval, including different temperature and pH, under OPLS-2005 force field using DESMOND suite. Following, post-dynamics structure parameters for the DNA junction were calculated and analyzed by comparison to the crystal structure. We show here that the self-assembly dynamics of DNA junction is mitigated by the temperature and pH sensitivities, and discloses peculiar structural properties as function of time. From this study it can be concluded on account of temperature sensitive and pH dependent behaviours, DNA junction periodic arrangements can willingly be synthesized and redeveloped for multiple uses like genetic biomarkers, DNA biosensor, DNA nanotechnology, DNA Zipper, etc. Furthermore, the pH dis-regulation behaviour may be used to trigger the functionality of DNA made drug-releasing nanomachines.

Drug repurposing for ligand-induced rearrangement of Sirt2 active site-based inhibitors via molecular modeling and quantum mechanics calculations.

Sirtuin 2 (Sirt2) nicotinamide adenine dinucleotide-dependent deacetylase enzyme has been reported to alter diverse biological functions in the cells and onset of diseases, including cancer, aging, and neurodegenerative diseases, which implicate the regulation of Sirt2 function as a potential drug target. Available Sirt2 inhibitors or modulators exhibit insufficient specificity and potency, and even partially contradictory Sirt2 effects were described for the available inhibitors. Herein, we applied computational screening and evaluation of FDA-approved drugs for highly selective modulation of Sirt2 activity via a unique inhibitory mechanism as reported earlier for SirReal2 inhibitor. Application of stringent molecular docking results in the identification of 48 FDA-approved drugs as selective putative inhibitors of Sirt2, but only top 10 drugs with docking scores > - 11 kcal/mol were considered in reference to SirReal2 inhibitor for computational analysis. The molecular dynamics simulations and post-simulation analysis of Sirt2-drug complexes revealed substantial stability for Fluphenazine and Nintedanib with Sirt2. Additionally, developed 3D-QSAR-models also support the inhibitory potential of drugs, which exclusively revealed highest activities for Nintedanib (pIC50 ≥ 5.90 µM). Conclusively, screened FDA-approved drugs were advocated as promising agents for Sirt2 inhibition and required in vitro investigation for Sirt2 targeted drug development.