We have embedded the hexameric triplet repeats (CAG)(6) and (CTG)(6) between two (GC)(3) domains to produce two 30-mer hairpins with the sequences d[(GC)(3)(CAG)(6)(GC)(3)] and d[(GC)(3)(CTG)(6)(GC)(3)]. This construct reduces the conformational space available to these repetitive DNA sequences. We find that the (CAG)(6) and (CTG)(6) repeats form stable, ordered, single-stranded structures. The...

Eukaryotic translation initiation factor 4A (elF4A) has been proposed to use the energy of ATP hydrolysis to remove RNA structure in the 5' untranslated region (UTR) of mRNAs, helping the 43S ribosomal complex bind to an mRNA and scan to find the 5'-most AUG initiator codon. We have examined the effect of changing the atomic composition and length of single-stranded oligonucleotides on binding ...

Hepatitis C virus NS3 helicase is an enzyme that unwinds double-stranded polynucleotides in an ATP-dependent reaction. It provides a promising target for small molecule therapeutic agents against hepatitis C. Design of such drugs requires a thorough understanding of the dynamical nature of the mechanochemical functioning of the helicase. Despite recent progress, the detailed mechanism of the co...

In addition to the helical nature of double-stranded DNA and RNA, single-stranded oligonucleotides can arrange themselves into tridimensional structures containing loops, bulges, internal hairpins and many other motifs. This ability has been used for more than two decades to generate oligonucleotide sequences, so-called aptamers, that can recognize certain metabolites with high affinity and spe...

Escherichia coli UvrD is a superfamily 1 DNA helicase and single-stranded DNA (ssDNA) translocase that functions in DNA repair and plasmid replication and as an anti-recombinase by removing RecA protein from ssDNA. UvrD couples ATP binding and hydrolysis to unwind double-stranded DNA and translocate along ssDNA with 3'-to-5' directionality. Although a UvrD monomer is able to translocate along s...

DNA is subject to oxidative damage due to radiation or by-products of cellular metabolism, thereby creating electron holes that migrate along the DNA stacks. A systematic computational analysis of the dependence of the electronic properties of nucleobase stacks on sequence and conformation was performed here, on the basis of single- and double-stranded homo-nucleobase stacks of 1-10 bases or 1-...

Bacterial α-2-macroglobulins have been suggested to function in defence as broad-spectrum inhibitors of host proteases that breach the outer membrane. Here, the X-ray structure of protease-cleaved Escherichia coli α-2-macroglobulin is described, which reveals a putative mechanism of activation and conformational change essential for protease inhibition. In this competitive mechanism, protease c...

COURSE INFORMATION The following text is a summary of a two-hour lecture sequence presented in the course, Advanced Medicinal Chemistry I. This course is required for all MS and PhD students in Duquesne University’s Medicinal Chemistry Graduate Program. It is also available as an elective for undergraduate students in their last semester of didactic work. The course emphasizes the basic chemica...

Bacterial transcription is initiated after RNA polymerase (RNAP) binds to promoter DNA, melts ~14 bp around the transcription start site and forms a single-stranded "transcription bubble" within a catalytically active RNAP-DNA open complex (RP(o)). There is significant flexibility in the transcription start site, which causes variable spacing between the promoter elements and the start site; th...

The Saccharomyces cerevisiae RNase III enzyme Rnt1p preferentially binds to double-stranded RNA hairpin substrates with a conserved (A/u)GNN tetraloop fold, via shape-specific interactions by its double-stranded RNA-binding domain (dsRBD) helix α1 to the tetraloop minor groove. To investigate whether conformational flexibility in the dsRBD regulates the binding specificity, we determined the ba...