X-ray and neutron scattering

Abstract:

The synthesis of four novel crystalline zeolitic imidazolate framework (ZIF) structures using a mixed-ligand approach is reported. The inclusion of both imidazolate and halogenated benzimidazolate-derived linkers leads to glass-forming behavior by all four structures. Melting temperatures are observed to depend on both electronic and steric effects. Solid-state NMR and terahertz (THz)/far-IR demonstrate the presence of a Zn-F bond for fluorinated ZIF glasses. In situ THz/far-IR spectroscopic techniques reveal the dynamic structural properties of crystal, glass, and liquid phases of the halogenated ZIFs, linking the melting behavior of ZIFs to the propensity of the ZnN₄ tetrahedra to undergo thermally induced deformation. The inclusion of halogenated ligands within metal-organic framework (MOF) glasses improves their gas-uptake properties.

Abstract:

HIV-1 protease is an essential therapeutic target for the design and development of antiviral inhibitors to treat AIDS. We used room temperature neutron crystallography to accurately determine hydrogen atom positions in several protease complexes with clinical drugs, amprenavir and darunavir. Hydrogen bonding interactions were carefully mapped to provide an unprecedented picture of drug binding to the protease target. We demonstrate that hydrogen atom positions within the enzyme catalytic site can be altered by introducing drug resistant mutations and by protonating surface residues that trigger proton transfer reactions between the catalytic Asp residues and the hydroxyl group of darunavir. When protein perdeuteration is not feasible, we validate the use of initial H/D exchange with unfolded protein and partial deuteration in pure D₂O with hydrogenous glycerol to maximize deuterium incorporation into the protein, with no detrimental effects on the growth of quality crystals suitable for neutron diffraction experiments.