Conjugation of poor inhibitors with surface binding groups: a strategy to improve inhibition

Conjugation of surface binding groups with inhibitors for carbonic anhydrase leads to the conversion of weak inhibitors to strong inhibitors.     

Baryogenesis and damping in nonminimal electroweak models

We calculate the baryon asymmetry of the Universe in the standard model of the electroweak theory with CP violation appropriate for simple extensions of the Higgs sector. The propagation of quarks of masses up to about 5 GeV are considered, taking into account the effect of damping rate. We find that the contribution of the b quark can still account for the observed baryon asymmetry to within the theoretical uncertainties of such models.

     

Non-linear vibrations of a harmonically excited autoparametric system

Harmonic forced vibration of a spring-mass-damper system with a parametrically excited pendulum hinged to the mass is investigated. Two types of restoring forces on the pendulum are considered. The method of harmonic balance is used to evaluate the system response. The results are also verified by numerical integration. Non-periodic system responses are possible if the excitation parameter is large. The performance of the pendulum as an absorber is also studied.     

Development of an affinity silica monolith containing alpha1-acid glycoprotein for chiral separations

An affinity monolith based on silica and containing immobilized alpha(1)-acid glycoprotein (AGP) was developed and evaluated in terms of its binding, efficiency and selectivity in chiral separations. The results were compared with data obtained for the same protein when used as a chiral stationary phase with HPLC-grade silica particles or monoliths based on a copolymer of glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA). The surface coverage of AGP in the silica monolith was 18% higher than that obtained with silica particles and 61% higher than that measured for a GMA/EDMA monolith. The higher surface area of the silica monolith gave materials that contained 1.5- to 3.6-times more immobilized protein per unit volume when compared to silica particles or a GMA/EDMA monolith. The retention, efficiency and resolving power of the AGP silica monolith were evaluated by injecting two chiral analytes onto this column (i.e., R/S-warfarin and R/S-propranolol). In each case, the AGP silica monolith gave higher retention plus better resolution and efficiency than AGP columns containing silica particles or a GMA/EDMA monolith. The AGP silica monolith also gave lower back pressures and separation impedances than these other materials. It was concluded that silica monoliths can be valuable alternatives to silica particles or GMA/EDMA monoliths when used with AGP as a chiral stationary phase.     

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.     

Effect of secondary decay on isoscaling: Results from the canonical thermodynamical model

The projectile fragmentation reactions using ⁵⁸Ni and ⁶⁴Ni beams at 140 MeV/n on targets ⁹Be and ¹⁸¹Ta are studied using the canonical thermodynamical model coupled with an evaporation code. The isoscaling property of the fragments produced is studied using both the primary and the secondary fragments and it is observed that the secondary fragments also respect isoscaling though the isoscaling parameters α and β changes. The temperature needed to reproduce experimental data with the secondary fragments is less than that needed with the primary ones. The canonical model coupled with the evaporation code successfully explains the experimental data for isoscaling for the projectile fragmentation reactions.     

A Central Limit Theorem for linear random fields

A Central Limit Theorem is proved for linear random fields when sums are taken over union of finitely many disjoint rectangles. The approach does not rely upon the use of Beveridge-Nelson decomposition and the conditions needed are similar in nature to those given by Ibragimov for linear processes. When specializing this result to the case when sums are being taken over rectangles, a complete analogue of the Ibragimov result is obtained for random fields with a lot of uniformity.     

Irreversible solvent-driven conversion in cyanometalate {Fe2Ni}n (n=2, 3) single-molecule magnets

Two cyano-bridged single-molecule magnets of {Fe(III)(4)Ni(II)(2)} and {Fe(III)(6)Ni(II)(3)} stoichiometry are described via their magnetic properties described in the frame of geometrical core distortions and orientations of their local anisotropy axes.