Ultrahigh resolution crystal structures of human carbonic anhydrases I and II complexed with "two-prong" inhibitors reveal the molecular basis of high affinity

The atomic-resolution crystal structures of human carbonic anhydrases I and II complexed with "two-prong" inhibitors are reported. Each inhibitor contains a benzenesulfonamide prong and a cupric iminodiacetate (IDA-Cu(2+)) prong separated by linkers of different lengths and compositions. The ionized NH(-) group of each benzenesulfonamide coordinates to the active site Zn(2+) ion; the IDA-Cu(2+) prong of the tightest-binding inhibitor, BR30, binds to H64 of CAII and H200 of CAI. This work provides the first evidence verifying the structural basis of nanomolar affinity measured for two-prong inhibitors targeting the carbonic anhydrases.     

Far field photoluminescence imaging of single AlGaN nanowire in the sub‐wavelength scale using confinement of polarized light

Till now the nanoscale focusing and imaging in the sub‐diffraction limit is achieved mainly with the help of plasmonic field enhancement by confining the light assisted with noble metal nanostructures. Using far field imaging technique, we have recorded polarized spectroscopic photoluminescence (PL) imaging of a single AlGaN nanowire (NW) of diameter ～100 nm using confinement of polarized light. It is found that the PL from a single NW is influenced by the proximity to other NWs. The PL intensity is proportional to 1/(l×d), where l and d are the average NW length and separation between the NWs, respectively. We suggest that the proximity induced PL intensity enhancement can be understood by assuming the existence of reasonably long lived photons in the intervening space between the NWs. A nonzero non‐equilibrium population of such photons may cause stimulated emission leading to the enhancement of PL emission with the intensity proportional to 1/(l×d). The enhancement of PL emission facilitates far field spectroscopic imaging of a single semiconductor AlGaN NW of sub‐wavelength dimension.

     

Inhibition of matrix metalloproteinase-9 by "multi-prong" surface binding groups

A novel strategy of blocking the active site accessibility of MMP-9 by "multi-prong" surface binding groups is described.     

an average “hole-potential” method for studying properties of molecules in excited states: a test calculation on thiophosgene

An average hole-potential method (AHP) for studying molecular electronic structures and properties in excited states is suggested. The improved virtual orbitals (IVOs) prepared by this method are adapted to all possible transitions on the average. AHP calculations performed on the excited states of thiophosgene at the CNDO/2 level yield encouraging results.     

On mass-independence of the minimal subtraction scheme in dimensional regularization II

A self-contained argument is given for the mass independence of the renormalization constants in the minimal subtraction scheme in dimensional regularization in a two mass theory (Yukawa theory). An extension to a theory containing more mass parameters seems straightforward.     

A clay-mediated eco-friendly thiocyanation of indoles and carbazoles

Indoles 1a-f and carbazoles 3a-c on treatment with ammonium thiocyanate on montmorillonite K10 clay at 80°C furnished the corresponding 3-thiocyanato derivatives 2a-f and 4a-c in good to high yields. Skatole 5 furnished the dimeric oxindole 6, which resulted from autoxidation.     

A study of the deterministic character of optical damage by femtosecond laser pulses and applications to nanomachining

A remarkable feature of material damage induced by short-pulsed lasers is that the energy threshold becomes deterministic for sub-picosecond pulses. This effect, coupled with the advent of kHz and higher repetition rate chirped pulse amplification systems, has opened the field of femtosecond machining. Yet the mechanism of optical breakdown remains unclear. By examining the damage threshold as a function of polarization, we find that, contrary to established belief, multiphoton ionization plays an insignificant role in optical breakdown. The polarization independence, combined with the observed precise and uniform dielectric breakdown threshold even for nanometer-scale features, leads us to conclude that the fundamental mechanism is self-terminated Zener-impact ionization, and that the deterministic and uniform damage threshold throughout the sample threshold stems from the uniform valence-electron density found in good-quality optical materials. By systematically exploring optical breakdown near threshold, we find that we can consistently machine features as small as 20 nm, demonstrating great promise for applications ranging from Micro ElectroMechanical Systems (MEMS) construction and microelectronics, to targeted disruption of cellular structures and genetic material. PACS 32.80.Rm; 77.22.Jp; 81.16.-c     

Local BRS transformations and OSp(3,1¦2) symmetry of Yang-Mills theories

We consider a certain local generalization of BRS transformations of Yang-Mills theory in which the anti-commuting parameter is space time dependent. While these are not exact symmetries, they do lead to a new nontrivial WT identity. We make a precise connection between the “local BRS” and the broken orthosymplectic symmetry recently found in superspace formulation of Yang-Mills theory by showing that the local BRS WT identity is precisely the WT identity obtained in the superspace formulation via a superrotation. This “local BRS” WT identity could lead to new consequences not contained in the usual BRS WT identity.     

Synthetic studies on the molybdenum cofactor: Total synthesis of pterindithiolenes by direct dithiolene formation from suitable pterin alkynes

A novel, efficient total synthesis of a series of pterindithiolenes (15, 16, 17 and 18) [(5,6-dihydro-[1,4]dithiin or 6,7-dihydro-5H-[1,4]dithiepin systems respectively for six and seven membered dithiolenes] has been reported. The six membered quinoxaline thioketal 9 and seven membered quinoxaline dithiolene 11 have also been synthesized from quinoxaline acetylenic alcohol 5 and the corresponding acetylenic ketone 10 respectively. The synthesis of five membered pterin thioketals 12 and 13 along with the conversion of 13 to the dithiolene 14 by the reaction with NBS is also reported.     

Structural analysis of charge discrimination in the binding of inhibitors to human carbonic anhydrases I and II

Despite the similarity in the active site pockets of carbonic anhydrase (CA) isozymes I and II, the binding affinities of benzenesulfonamide inhibitors are invariably higher with CA II as compared to CA I. To explore the structural basis of this molecular recognition phenomenon, we have designed and synthesized simple benzenesulfonamide inhibitors substituted at the para position with positively charged, negatively charged, and neutral functional groups, and we have determined the affinities and X-ray crystal structures of their enzyme complexes. The para-substituents are designed to bind in the midsection of the 15 A deep active site cleft, where interactions with enzyme residues and solvent molecules are possible. We find that a para-substituted positively charged amino group is more poorly tolerated in the active site of CA I compared with CA II. In contrast, a para-substituted negatively charged carboxylate substituent is tolerated equally well in the active sites of both CA isozymes. Notably, enzyme-inhibitor affinity increases upon neutralization of inhibitor charged groups by amidation or esterification. These results inform the design of short molecular linkers connecting the benzenesulfonamide group and a para-substituted tail group in "two-prong" CA inhibitors: an optimal linker segment will be electronically neutral, yet capable of engaging in at least some hydrogen bond interactions with protein residues and/or solvent. Microcalorimetric data reveal that inhibitor binding to CA I is enthalpically less favorable and entropically more favorable than inhibitor binding to CA II. This contrasting behavior may arise in part from differences in active site desolvation and the conformational entropy of inhibitor binding to each isozyme active site.