George K. Papadopoulos

Molecular dynamics (MD) simulations were conducted in order to investigate the effect of the naturally occurring point mutations of the transcription factor (TF) sex-determining region Y (SRY) on the structure and dynamics of the SRY-DNA complex. The normal SRY, along with the two mutants I13T and G40R, comprising point mutations on the SRY chain, which have been clinically identified in patients with sex developmental disorders, were modeled as DNA complexes. Our modeling work aims at elucidating atomic-level structural determinants of the aberrant SRY-DNA complexation by means of mu s-long MD. The results suggest that the observed disorders brought about by the G40R-DNA and I13T-DNA may arise predominantly from the destabilization of the complex being in accord with in vitro assays found elsewhere and from modifications of the DNA bending as revealed in this study. Comparative potential of mean force computations, over a sequence of short separation distances for the three complexes, verified a higher stability of the normal SRY-DNA. Examining the way the SRY mutations modulate the SRY-DNA complex dynamics at the microscopic level is important also toward elucidating molecular determinants of function for proteins capable of binding to DNA.

A DNA-based artificial metalloenzyme (ArM) consisting of a copper(II) complex of 4,4′-dimethyl-2,2′-bipyridine (dmbipy-Cu) bound to double-stranded DNA (dsDNA) as short as 8 base pairs with only 2 contiguous central pairs (G for guanine and C for cytosine) catalyzes the highly enantioselective Diels–Alder reaction, Michael addition, and Friedel–Crafts alkylation in water. Molecular simulations indicate that these minimal sequences provide a single site where dmbipy-Cu is groove-bound and able to function as an enantioselective catalyst. Enantioselective preference inverts when d-DNA is replaced with l-DNA. When the DNA is conjugated to a hydrophobic tail, the obtained ArMs exhibit enantioselective performance in a methanol–water mixture superior to that of non-amphiphilic dsDNA, and dsDNA-amphiphiles with more complex G•C-rich sequences.

The engineering issues pertaining to nanoparticle systems toward targeted gene therapies have not been fully probed. Recent experiments have identified specific structural characteristics of a novel class of lipopeptides (LP) that may lead to potent nanocarriers intended as RNAi therapeutics; albeit the molecular mechanism that underlies their performance remains unexplored. We conducted molecular dynamics simulations in atomistic detail coupled with free energy computations to study the dynamics and thermodynamics of an acrylate- and an epoxide-derived LP, members of the aforesaid class, upon their binding to siRNA in aqueous solution aiming at examining structure-potency relations. We found that the entropic part of the free energy of binding predominates; yet, the first LP class tends to disrupt the Watson-Crick base pairing of siRNA, whereas the latter leaves the double helix intact. Moreover, the identified tug-of-war effect between LP-water and LP-siRNA hydrogen bonding in the supramolecular complex can underpin synthesis routes toward tuning the association dynamics. Our simulations on two diastereomers of the epoxide-derived LP showed significant structural and energetics differences upon binding, as a result of steric effects imposed by the different absolute configurations at their chiral centers. These findings may serve as crucial design parameters toward modulating the interplay between complex stability and ease of releasing the nucleic acid drug into the cell.

Aluminium isophthalate CAU-10-H [Al(OH)(benzene-1,3-dicarboxylate)]·nH₂O exhibits water adsorption characteristics which make it a promising adsorbent for application in heat-exchange processes. Herein we prepared a stable coating of this MOF and evaluated its long-term stability under closed-cycle conditions for 10 000 water adsorption and desorption cycles, which are typical lifetimes for adsorption heat storage (AHS) applications. No degradation of the adsorption capacity could be observed which makes CAU-10-H the most stable MOF under these humid cycling conditions reported until now. Moreover, thermophysical properties like thermal conductivity and heat of adsorption were directly measured. In order to identify the structural features associated with the adsorption behaviour, the structural differences between the dry and the water loaded CAU-10-H were studied by Rietveld refinements and second harmonic generation (SHG) microscopy. The observed transition of space group symmetry from I4₁ to I4₁/amd between the humid and dry forms is induced by the adsorption/desorption of water into/out of the MOF channels. This originates from a torsional motion around the C–C bond between the carboxylate groups and the aromatic ring in half of the linker molecules. These observations are in excellent agreement with molecular dynamics simulations which confirm the energetic benefit of this transition.

Die Diffusion von Wasser in SAPO‐34 wurde im Temperatur‐ und Beladungsbereich, der für Anwendungen in der adsorptiven Wärmetransformation relevant ist, experimentell untersucht. Korrigierte Diffusionskoeffizienten aus IR‐Messungen, die direkt an Adsorptionsschichten auf einem Aluminiumträger während der Adsorption und Desorption gemessen wurden und Selbstdiffusionskoeffizienten aus NMR‐Untersuchungen im thermodynamischen Gleichgewicht sind untereinander konsistent, weitgehend beladungsunabhängig und etwa zwei Größenordnungen kleiner als die Diffusion des flüssigen Wassers bei gleicher Temperatur. Die Temperaturabhängigkeit der Wasserdiffusion im SAPO‐34 kann mit einer Aktivierungsenergie von (11 ± 2) kJ mol⁻¹ beschrieben werden.