DFT-based Conformational Analysis of a Phospholipid Molecule (DMPC)

The conformational space of the dimyristoyl phosphatidylcholine (DMPC) molecule has been studied using Density Functional Theory (DFT), augmented with a damped empirical dispersion energy term (DFT-D). Fourteen ground-state isomers have been found with total energies within less than 1 kcal/mol. Despite differences in combinations of their torsion angles, all these conformers share a common geometric profile, which includes a balance of attractive, repulsive and constraint forces between and within specific groups of atoms. The definition of this profile fits with most of the structural characteristics deduced from measured NMR properties of DMPC solutions. The calculated vibrational spectrum of the molecule is in good agreement with experimental data obtained for DMPC bilayers. These results support the idea that DMPC molecules preserve their individual molecular structures in the various assemblies.Comment: 31 pages, 6 Tables, 4 Figure

Identification of durable and non-durable FeN x sites in Fe–N–C materials for proton exchange membrane fuel cells

While Fe–N–C materials are a promising alternative to platinum for catalysing the oxygen reduction reaction in acidic polymer fuel cells, limited understanding of their operando degradation restricts rational approaches towards improved durability. Here we show that Fe–N–C catalysts initially comprising two distinct FeNx sites (S1 and S2) degrade via the transformation of S1 into iron oxides while the structure and number of S2 were unmodified. Structure–activity correlations drawn from end-of-test 57Fe Mössbauer spectroscopy reveal that both sites initially contribute to the oxygen reduction reaction activity but only S2 substantially contributes after 50 h of operation. From in situ 57Fe Mössbauer spectroscopy in inert gas coupled to calculations of the Mössbauer signature of FeNx moieties in different electronic states, we identify S1 to be a high-spin FeN4C12 moiety and S2 a low- or intermediate-spin FeN4C10 moiety. These insights lay the groundwork for rational approaches towards Fe–N–C cathodes with improved durability in acidic fuel cells. [Figure not available: see fulltext.

Mixed-symmetry octupole and hexadecapole excitations in N=52 isotones

In addition to the well-established quadrupole mixed-symmetry states, octupole and hexadecapole excitations with mixed-symmetry character have been recently proposed for the N = 52 isotones 92Zr and 94Mo. We performed two inelastic proton-scattering experiments to study this kind of excitations in the heaviest stable N = 52 isotone 96Ru. From the combined experimental data of both experiments absolute transition strengths were extracted

Combinatorial–computational–chemoinformatics (C3) approach to finding and analyzing low-energy tautomers

Finding the most stable tautomer or a set of low-energy tautomers of molecules is critical in many aspects of molecular modelling or virtual screening experiments. Enumeration of low-energy tautomers of neutral molecules in the gas-phase or typical solvents can be performed by applying available organic chemistry knowledge. This kind of enumeration is implemented in a number of software packages and it is relatively reliable. However, in esoteric cases such as charged molecules in uncommon, non-aqueous solvents there is simply not enough available knowledge to make reliable predictions of low energy tautomers. Over the last few years we have been developing an approach to address the latter problem and we successfully applied it to discover the most stable anionic tautomers of nucleic acid bases that might be involved in the process of DNA damage by low-energy electrons and in charge transfer through DNA. The approach involves three steps: (1) combinatorial generation of a library of tautomers, (2) energy-based screening of the library using electronic structure methods, and (3) analysis of the information generated in step (2). In steps 1–3 we employ combinatorial, computational and chemoinformatics techniques, respectively. Therefore, this hybrid approach is named “Combinatorial*Computational*Chemoinformatics”, or just abbreviated as C3 (or C-cube) approach. This article summarizes our developments and most interesting methodological aspects of the C3 approach. It can serve as an example how to identify the most stable tautomers of molecular systems for which common chemical knowledge had not been sufficient to make definite predictions

RNAi-Mediated c-Rel Silencing Leads to Apoptosis of B Cell Tumor Cells and Suppresses Antigenic Immune Response In Vivo

c-Rel is a member of the Rel/NF-κB transcription factor family and is predominantly expressed in lymphoid and myeloid cells, playing a critical role in lymphocyte proliferation and survival. Persistent activation of the c-Rel signal transduction pathway is associated with allergies, inflammation, autoimmune diseases, and a variety of human malignancies. To explore the potential of targeting c-Rel as a therapeutic agent for these disorders, we designed a small interfering RNA (siRNA) to silence c-Rel expression in vitro and in vivo. C-Rel-siRNA expression via a retroviral vector in a B cell tumor cell line leads to growth arrest and apoptosis of the tumor cells. Silencing c-Rel in primary B cells in vitro compromises their proliferative and survival response to CD40 activation signals, similar to the impaired response of c-Rel knockout B cells. Most important, in vivo silencing of c-Rel results in significant impairment in T cell-mediated immune responses to antigenic stimulation. Our study thus validates the efficacy of c-Rel-siRNA, and suggests the development of siRNA-based therapy, as well as small molecular inhibitors for the treatment of B cell tumors as well as autoimmune diseases