Abstract:The implementation of the n-center electron delocalization indices, n-DIs, and n-order electron localization indices, n-LIs, within the framework of the quantum theory of atoms in molecules, QTAIM, is performed. n-DIs are shown to be very useful to study the local aromaticity in monocyclic and polycyclic compounds. Total and p n-DIs from n ¼ 4 to 7 were computed for a series of typical 4, 5, 6, and 7-center aromatic and antiaromatic rings. For n ! 5 the p n-DI accounts for the 95% of the total n-DI and can be employed alone to measure the aromaticity. A scaling factor on the n-DIs is required in order to compare the aromaticity of [5c-6e] and [6c-6e] rings, the same correction allows to estimate the relative aromatic stabilization of polycyclic compounds using the sum of its values for individual rings. This is called Effective Scaled Electron Delocalization, ESED. The comparison with other aromaticity indices reflects a good correlation between ESED and both resonance energies, and HOMA indices. The most important differences between scaled p n-DIs and NICS(0) indices are found for compounds that contain rings with different number of centers or p electrons.

Combining molecular dynamics (MD) in a hydrated phospholipids (DOPC) bilayer, Monte Carlo search, and synthesis of locked nucleotide analogues we discovered that the Southern conformation of the ribose is preferred for ligand recognition by the P2Y 6 receptor. 2′-Deoxy-(S)-methanocarbaUDP was found to be a full agonist of the receptor and displayed a 10-fold higher potency than the corresponding flexible 2′-deoxyUDP. MD results also suggested a conformational change of the second extracellular loop consequent to agonist binding.P2Y receptors are a family of class A G protein-coupled receptors (GPCRs), variously activated by extracellular purine and pyrimidine nucleotides. 1,2 The family is composed of two distinct subgroups, which differ in overall sequence similarity, mechanism of ligand recognition, and coupling to second messengers. The P2Y 1 -like subgroup encompasses the P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 receptors, which couple mainly to the stimulation of phospholipase C (PLC) via G q . On the other hand, the P2Y 12 -like subgroup encompasses the P2Y 12 , P2Y 13 , and P2Y 14 receptors, which couple mainly to the inhibition of adenylyl cyclase (AC) via G i . The P2Y 6 receptor is the only P2Y receptor whose natural agonist is uridine-5′-diphosphate (UDP, 1). It is the least studied subtype of the P2Y 1 -like subgroup, due to the lack of potent and selective ligands. It has recently been shown that the activation of the P2Y 6 receptor induces Ca 2+ and Cl − secretion in mouse trachea. Hence, P2Y 6 agonists may be useful to stimulate electrolyte transport in the airways of cystic fibrosis patients. 3It is known that the five-membered ring of the ribose moiety of nucleosides and nucleotides can adopt a range of conformations, which can be exhaustively described by two parameters indicative of puckering: P (phase angle of pseudorotation, schematically represented as a pseudorotational cycle) and θ (puckering amplitude). 4,5 Using conformationally-locked nucleotide analogues, we deduced a preference for the Northern (N) hemisphere of the pseudorotational cycle (2′-exo, 3′-endo) for the P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 11 receptors. 4,6, 7,8 However, the UDP analogue 2 locked in the (N) conformation by a (N)-methanocarba Figure 1). 7 Hence, prior to this work, the P2Y 6 receptor has been the most elusive subtype of the P2Y 1 -like receptors and the conformation of the ribose moiety of UDP required for the recognition of the ligand was not established.Here we report the discovery of the biologically-active conformation of the sugar moiety of UDP, which we accomplished by means of an interdisciplinary approach combining advanced molecular modeling techniques with the synthesis of conformationally locked nucleotide analogs. This finding represents a breakthrough toward the understanding of the biology of the P2Y 6 receptor, as it may be the key to the design of the long needed pharmacological tools.To obtain a refined model of the P2Y 6 receptor that could be exploited to identify the conformation ...

A new method for biolistic delivery of nucleic acids using a combination of cationic micro-and nanoparticles is reported. The new method is simpler to perform than the conventional calcium/ spermidine-based formulations and shows eleven-fold improved nucleic acid binding capacity and dose-dependent performance both for in vitro and in vivo applications relative to either the conventional preparation or our recently reported direct cationic microparticle method. These features may enable higher throughput gene delivery and genetic immunization programs and open new venues for biolistic delivery method.