Multiple Stimuli Triggered Structural Isomerization of Copper Iodide-pyridine Crystals

Copper based coordination materials possess the ability to exhibit changes of their physico-chemical properties in response to external stimuli. Recent researches related to Cu(I) complexes have revealed the external stimuli...

Data-Driven Reaction Coordinate Discovery in Overdamped and non-Conservative Systems: Application to Optical Matter Structural Isomerization

Powerful technique as it is to study the collective fluctuations and structural transitions in under-damped conservative systems, normal mode analysis cannot be applied to the optical matter (OM) system, an overdamped system subject to non-conservative forces, which consists of (nano-)particle constituents in solution that can self-organize into ordered arrays bound by electrodynamic interactions. We propose a data-driven approach based on principal component analysis (PCA) of deviations from a reference structure to determine the soft collective modes of non-conservative overdamped systems, such as OM structures, and harmonic linear discriminant analysis (HLDA) of time trajectories to estimate the reaction coordinate for structural transitions, which is demonstrated for structural isomerization of a six-particle OM system. The reaction coordinate we discover is in accord with committor analysis and the identified mechanism is in agreement with experiment. The PCA-HLDA approach to data-driven discovery of reaction coordinates aids in the understanding of non-conservative and overdamped systems.

Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease

A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer’s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β–amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.

Accounting for RNA polymerase heterogeneity reveals state switching and two distinct long-lived backtrack states escaping through cleavage

ABSTRACTPausing by bacterial RNA polymerase (RNAp) is vital in the recruitment of regulatory factors, RNA folding, and coupled translation. While backtracking and intra-structural isomerization have been proposed to trigger pausing, our understanding of backtrack-associated pauses and catalytic recovery remains incomplete. Using high-throughput magnetic tweezers, we examined the E. coli RNAp transcription dynamics over a wide range of forces and NTP concentrations. Dwell-time analysis and stochastic modeling identified, in addition to a short-lived elemental pause, two distinct long-lived backtrack pause states differing in recovery rates. We further identified two stochastic sources of transcription heterogeneity: alterations in short-pause frequency that underlie elongation-rate switching, and RNA cleavage deficiency that underpins different long-lived backtrack states. Together with effects of force and Gre factors, we demonstrate that recovery from deep backtracks is governed by intrinsic RNA cleavage rather than diffusional Brownian dynamics. We introduce a consensus mechanistic model that unifies our findings with prior models.

Direct observation of the intermediate in an ultrafast isomerization

Using a combination of two-dimensional infrared (2D IR) and variable temperature Fourier transform infrared (FTIR) spectroscopies the rapid structural isomerization of a five-coordinate ruthenium complex is investigated.