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.
Transfer
RNA remains to be a mysterious molecule of the cell repertoire.
With its modified bases and selectivity of codon recognition, it remains
to be flexible inside the ribosomal machinery for smooth and hassle-free
protein biosynthesis. Structural changes occurring in tRNA due to
the presence or absence of wybutosine, with and without Mg2+ ions, have remained a point of interest for structural biologists.
Very few studies have come to a conclusion correlating the changes
either with the structure and flexibility or with the codon recognition.
Considering the above facts, we have implemented molecular modeling
methods to address these problems using multiple molecular dynamics
(MD) simulations of tRNAPhe along with codons. Our results
highlight some of the earlier findings and also shed light on some
novel structural and functional aspects. Changes in the stability
of tRNAPhe in native or codon-bound states result from
the conformations of constituent nucleotides with respect to each
other. A smaller change in their conformations leads to structural
distortions in the base-pairing geometry and eventually in the ribose-phosphate
backbone. MD simulation studies highlight the preference of UUC codons
over UUU by tRNAPhe in the presence of wybutosine and Mg2+ ions. This study also suggests that magnesium ions are required
by tRNAPhe for proper recognition of UUC/UUU codons during
ribosomal interactions with tRNA.
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.
The
rapid outbreak of SARS-Coronavirus 2 (SARS-CoV-2) caused a serious global
public health threat. The spike ‘S’ protein of SARS-CoV-2 and ACE2 of the host
cell are being targeted to design and discover new drugs to control Covid-19
disease. Similarly, a transmembrane serine protease, TMPRSS2 of the host cell
has been found to play a significant role in proteolytic cleavage of viral
spike protein priming to the receptor ACE2 present in human cell. However,
three dimensional structure and inhibition mechanism of TMPRSS2 is yet to be explored
experimentally. Hence, in the present study we have generated a homology model
of TMPRSS2 and studied its binding properties with experimentally studied
inhibitors <i>viz.</i> Camostat mesylate, Nafamostat and Bromhexine
hydrochloride (BHH) using molecular docking technique. Docking analysis
revealed that the Camostat mesylate and its structural analogue Nafamostat
interacts strongly with residues His296, Ser441 and Asp435 present in catalytic
triad of TMPRSS2. However, BHH interacts with Gln438 and other residues present
in the active site pocket of TMPRSS2 through hydrophobic contacts effectively.
Thus, these results revealed the inhibition mechanism of TMPRSS2 by known
inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride in detail
at the molecular level. However, Camostat mesylate shows strong binding as
compared to other two inhibitors. This structural information could also be
useful to design and discover new inhibitors of TMPRSS2, which may be helpful
to prevent the entry to SARS-Coronavirus 2 in human cell.
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