No abstract

Mycobacterium tuberculosis is a Gram positive, acid-fast bacteria belonging to genus Mycobacterium, is the leading causative agent of most cases of tuberculosis. The pathogenicity of the bacteria is enhanced by its developed DNA repair mechanism which consists of machineries such as nucleotide excision repair. Nucleotide excision repair consists of excinuclease protein UvrABC endonuclease, multi-enzymatic complex which carries out repair of damaged DNA in sequential manner. UvrC protein is a part of this complex and thus helps to repair the damaged DNA of M. tuberculosis. Hence, structural bioinformatics study of UvrC protein from M. tuberculosis was carried out using homology modeling and molecular docking techniques. Assessment of the reliability of the homology model was carried out by predicting its secondary structure along with its model validation. The predicted structure was docked with the ATP and the interacting amino acid residues of UvrC protein with the ATP were found to be TRP539, PHE89, GLU536, ILE402 and ARG575. The binding of UvrC protein with the DNA showed two different domains. The residues from domain I of the protein VAL526, THR524 and LEU521 interact with the DNA whereas, amino acids interacting from the domain II of the UvrC protein included ARG597, GLU595, GLY594 and GLY592 residues. This predicted model could be useful to design new inhibitors of UvrC enzyme to prevent pathogenesis of Mycobacterium and so the tuberculosis.

Aggregation of amyloid beta (Aβ) peptides leads to formation of fibrilar, soluble oligomers, and their deposition is a key event in progression of Alzheimer’s disease (AD). Recent experimental studies of Arg-Arg-7-amino-4-trifluoromethylcoumarin (RR-AFC) showed significant Aβ aggregation inhibition, but its molecular mechanism is not yet clear. Hence, the present study aims at exploring the underlying mechanism of destabilization and inhibition of aggregation of the Aβ protofibril by RR-AFC at the molecular level. Molecular docking analysis shows that RR-AFC binds to chain A of the Aβ protofibril through hydrogen bonding interactions. Comparative molecular dynamics simulations depict the binding of RR-AFC at the edge of chain A, and its partially inserted conformation at the hydrophobic core destabilizes the Aβ protofibril. Its binding causes loss of hydrophobic contacts, leading to a partial opening of tightly packed β-sheet protofibrils. The hydration effect of salt bridge between the amino group of Lys28 and the oxygen atom of RR-AFC contributes in destabilization of Aβ protofibrils. Binding free energy calculations of RR-AFC and the Aβ protofibril showed that van der Waals interactions are dominant over the others. Thus, our results revealed that RR-AFC interacts mainly with the hydrophobic core along with positively charged residues of the Aβ protofibril for effective destabilization. Thus, this structural information could be useful to design new inhibitors to control the aggregation of Aβ protofibrils in AD patients.

No abstract

Transfer RNAs (tRNAs) contain various uniquely modified nucleosides thought to be useful for maintaining the structural stability of tRNAs. However, their significance for upholding the tRNA structure has not been investigated in detail at the atomic level. In this study, molecular dynamic simulations have been performed to assess the effects of methylated nucleic acid bases, N (2)-methylguanosine (m(2)G) and N (2)-N (2)-dimethylguanosine (m 2 (2) G) at position 26, i.e., the hinge region of E. coli tRNA(Phe) on its structure and dynamics. The results revealed that tRNA(Phe) having unmodified guanosine in the hinge region (G26) shows structural rearrangement in the core of the molecule, resulting in lack of base stacking interactions, U-turn feature of the anticodon loop, and TΨC loop. We show that in the presence of the unmodified guanosine, the overall fold of tRNA(Phe) is essentially not the same as that of m(2)G26 and m 2 (2) G26 containing tRNA(Phe). This structural rearrangement arises due to intrinsic factors associated with the weak hydrogen-bonding patterns observed in the base triples of the tRNA(Phe) molecule. The m(2)G26 and m 2 (2) G26 containing tRNA(Phe) retain proper three-dimensional fold through tertiary interactions. Single-point energy and molecular electrostatics potential calculation studies confirmed the structural significance of tRNAs containing m(2)G26 and m 2 (2) G26 compared to tRNA with normal G26, showing that the mono-methylated (m(2)G26) and dimethylated (m 2 (2) G26) modifications are required to provide structural stability not only in the hinge region but also in the other parts of tRNA(Phe). Thus, the present study allows us to better understand the effects of modified nucleosides and ionic environment on tRNA folding.