1,721,077 research outputs found
Oligomeric states of an Influenza-encoded PB1-F2 viroporin
No full text<p>The dataset contains input files to run all simuations and analyses.</p>
Rational Design of Acridine-Based Ligands with Selectivity for Human Telomeric Quadruplexes
No full textStructure-based modeling methods have been used to design a series of disubstituted triazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs. A focused library of these compounds was prepared using click chemistry and the selectivity concept was validated against two promoter quadruplexes from the c-kit gene with known molecular structures, as well as with duplex DNA using a FRET-based melting method. Lead compounds were found to have reduced effects on the thermal stability of the c-kit quadruplexes and duplex DNA structures. These effects were further explored with a series of competition experiments, which confirmed that binding to duplex DNA is very low even at high duplex:telomeric quadruplex ratios. Selectivity to the c-kit quadruplexes is more complex, with some evidence of their stabilization at increasing excess over human telomeric quadruplex DNA. Selectivity is a result of the dimensions of the triazole-acridine compounds; and in particular the separation of the two alkyl-amino terminal groups. Both lead compounds also have selective inhibitory effects on the proliferation of cancer cell lines compared to a normal cell line, and one has been shown to inhibit the activity of the telomerase enzyme, which is selectively expressed in tumor cells, where it plays a role in maintaining telomere integrity and cellular immortalization
Dynamic structural clustering of Class D β-Lactamases using Molecular simulations and Deep Learning
No full textClass D β-lactamases (DBLs) have gained clinical significance as major contributors to antimicrobial resistance, particularly through carbapenem hydrolysis. While their structural flexibility is increasingly recognized as central to their activity, existing studies of DBL dynamics are fragmented: they focus on individual enzymes, employ inconsistent residue numbering, and thus remain difficult to compare.
This thesis addresses these challenges in three stages. First, a literature consistent annotation framework is introduced. Using OXA-48 as a reference, the SAND (Structural Alignment-based Numbering of DBLs) scheme is developed together with a consensus secondary structure annotation, enabling homologous residues and elements to be consistently identified across the family. This framework resolves inconsistencies in the literature, supports reproducible analyses, and provides a resource for both experimental researchers and AI-based text/data mining tools.
Second, a comparative dynamics study is conducted with the aim of filling the gap of dynamic knowledge among different OXAs and identifying measurable dynamical properties that can be linked to substrate profiles and functional phenotypes of DBLs. Enhanced sampling through adaptive bandit molecular dynamics simulations is used to explore conformational landscapes across representative enzymes, revealing conserved motifs and subfamily-specific differences in loop flexibility and hydrophobic bridge formation.
Finally, deep learning is applied to analyze these large-scale simulations. Convolutional variational autoencoders were trained on inter-residue distance matrices, and the resulting latent representations were projected into low-dimensional spaces. This approach enabled the detection and interpretation of clustering patterns corresponding to metastable conformational states, which were mapped back to structural and functional determinants of substrate specificity.
By integrating structural standardization, comparative dynamics, and deep learning–based interpretation, this thesis establishes a coherent framework linking sequence, structure, dynamics, and function in DBLs. The results consolidate fragmented knowledge, provide mechanistic insights into functional variability, and offer a foundation for rational inhibitor design
Structural Insights into the Quadruplex-Duplex 3 ' Interface Formed from a Telomeric Repeat: A Potential Molecular Target
Get PDFWe report here on an X-ray crystallographic and molecular modeling investigation into the complex 3′ interface formed between putative parallel stranded G-quadruplexes and a duplex DNA sequence constructed from the human telomeric repeat sequence TTAGGG. Our crystallographic approach provides a detailed snapshot of a telomeric 3′ quadruplex–duplex junction: a junction that appears to have the potential to form a unique molecular target for small molecule binding and interference with telomere-related functions. This unique target is particularly relevant as current high-affinity compounds that bind putative G-quadruplex forming sequences only rarely have a high degree of selectivity for a particular quadruplex. Here DNA junctions were assembled using different putative quadruplex-forming scaffolds linked at the 3′ end to a telomeric duplex sequence and annealed to a complementary strand. We successfully generated a series of G-quadruplex–duplex containing crystals, both alone and in the presence of ligands. The structures demonstrate the formation of a parallel folded G-quadruplex and a B-form duplex DNA stacked coaxially. Most strikingly, structural data reveals the consistent formation of a TAT triad platform between the two motifs. This triad allows for a continuous stack of bases to link the quadruplex motif with the duplex region. For these crystal structures formed in the absence of ligands, the TAT triad interface occludes ligand binding at the 3′ quadruplex–duplex interface, in agreement with in silico docking predictions. However, with the rearrangement of a single nucleotide, a stable pocket can be produced, thus providing an opportunity for the binding of selective molecules at the interface
Biaryl polyamides as a new class of DNA quadruplex-binding ligands
No full textWe report a novel class of biaryl polyamides highly selective for G-quadruplex DNA, and with significant cytotoxicity in several cancer cell lines; they form planar U-shaped structures that match the surface area dimensions of a terminal G-quartet in quadruplex structures rather than the grooves of duplex DNA
Deciphering the co-evolutionary dynamics of L2 β-lactamases via Deep learning
No full text<p>The data set contains all input files used to run the simulations and the trajectories obtained from the simulation runs.</p>
In vivo investigation of (2-hydroxypropyl)-β-cyclodextrin-based formulation of spironolactone in aqueous solution for paediatric use
Get PDFSpironolactone (SPL), a potent anti-aldosterone steroidal drug used to treat several diseases in paediatric patients (e.g., hypertension, primary aldosteronism, Bartter’s syndrome, and congestive heart failure), is not available in child-friendly dosage forms, and spironolactone liquids have been reported to be unpalatable. Aiming to enhance SPL solubility in aqueous solution and overcome palatability, herein, the effects of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CyD) were thoroughly investigated on solubilisation in water and on masking the unpleasant taste of SPL in vivo. Although the complexation of SPL with HP-β-CyD was demonstrated through phase solubility studies, Job’s plot, NMR and computational docking studies, our in vivo tests did not show significant effects on taste aversion. Our findings, on the one hand, suggest that the formation of an inclusion complex of SPL with HP-β-CyD itself is not necessarily a good indicator for an acceptable degree of palatability, whereas, on the other hand, they constitute the basis for investigating other cyclodextrin-based formulations of the poorly water-soluble steroidal drug, including solid dosage forms, such as spray-dried powders and orodispersible tablets
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Surface area accessibility and the preferred topology of telomeric DNA quadruplex-ligand complexes.
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