Serpins exhibit a range of physiological roles and can contribute to certain disease states dependent on their various conformations. Understanding the mechanisms of the large-scale conformational reorganizations of serpins may lead to a better understanding of their roles in various cardiovascular diseases. We have studied the serpin, plasminogen activator inhibitor 1 (PAI-1), in both the active and the latent state and found that anionic halide ions may play a role in the active-to-latent structural transition. Crystallographic analysis of a stable mutant form of active PAI-1 identified an anion-binding site between the central beta-sheet and a small surface domain. A chloride ion was modeled in this site, and its identity was confirmed by soaking crystals in a bromide-containing solution and calculating a crystallographic difference map. The anion thus located forms a 4-fold ligated linchpin that tethers the surface domain to the central beta-sheet into which the reactive center loop must insert during the active-to-latent transition. Timecourse experiments measuring active PAI-1 stability in the presence of various halide ions showed a clear trend for stabilization of the active form with F(-) > Cl(-) > Br(-) >> I(-). We propose that the "stickiness" of this pin (i.e., the electronegativity of the anion) contributes to the energetics of the active-to-latent transition in the PAI-1 serpin.
This research contribution addrcsscs micromixing in polymer blcnds that exhibit strong intermolecular association. Specific interactions between dissimilar blend components are detected via high-resolution solid state proton and carbon-13 NMR spectroscopy. The isotropic chemical shifts of the critical component provide strong evidence that molecular complexes form. NM R spectral differences between the blends versus the undiluted components arise from crystal structure modifications (if appropriate), conformational changcs, hydrogen bonding, d-metal coordination, or altered packing gcomctrics that occur concomitantly with thc mixing process. More convincing evidence that two components of a strongly interacting blend reside in a near-neighbor environment is obtained from the measurement of proton spin diffusion between dissimilar species. Proton spin diffusion is measured directly via the high-resolution CRAMPS cxperimcnt (Combined Rotation And Multiple Pulse Spectroscopy) in a homogcncous solid solution of poly(cthylenc oxide) and rcsorcinol, and indirectly via thc carbon-13 spin system in a modified version of the Goldman-Shen experiment for microphasc-scparatcd ionic and tri-block copolymers. One of thc primary objcctivcs of this rcscarch cndcavor is to bridge the gap between macroscopic and site-specific probes of phase behavior and strong interaction in mixtures that form homogeneous solid solutions or coordination complexes. In this respect, results from a macroscopic phase of the polymer-blend research are included in this contribution. Thermal and mechanical properties are measured for strongly interacting systems, whose interaction sites arc characterized via solid state NMR. Metal-ligand coordination in blends of nickel acetatc with poly(4-vinylpyridinc) produces an extraordinary synergistic effect on the glass transition response. The maximum increase in blend relative to the undiluted polymcr is in the order of 100 C. Coordination bctwccn thc nitrogcn lonc pair in poly(4-vinylpyridinc) and the zinc cation in DuPont's SURLYNTM ionomers produces a 15% enhancement in mcchanical fracture stress rclativc to thc undiluted ionomer. The succcss of our structure-property relationship schcmc described hcrein, which bridges microscopic detection of site-specific interactions (via NMR) with practical macroscopic (DSC and strcss-strain) mcasurcmcnts, dcpcnds upon our ability to understand material propcrtics at a lcvcl whcrc continuum hypothcscs arc no longer valid. K c j . i i w t l .~: solid statc N M R and FTI R, polymcr blcnds, phasc-scparatcd copolymers, transition-metal coordination, thcrmal and mechanical properties, phase behaviour.
a preneutralizer tank and an ammonia scrubber. Recycle requirement for grades such as 18-46-0 and 21-53-0 is relatively low, about 2.5 pounds per pound of product, because the process takes advantage of the change in solubility of ammonium phosphate with the NH3:H3PC)4 mole ratio to assist in control of granulation. The preneutralizer is operated near the NH3: -H3P04 mole ratio giving maximum solubility of ammonium phosphate to obtain the most concentrated slurry
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