Room Temperature Neutron Crystallography of Drug Resistant HIV‑1 Protease Uncovers Limitations of X‑ray Structural Analysis at 100 K

HIV-1 protease inhibitors are crucial for treatment of HIV-1/AIDS, but their effectiveness is thwarted by rapid emergence of drug resistance. To better understand binding of clinical inhibitors to resistant HIV-1 protease, we used room-temperature joint X-ray/neutron (XN) crystallography to obtain an atomic-resolution structure of the protease triple mutant (V32I/I47V/V82I) in complex with amprenavir. The XN structure reveals a D⁺ ion located midway between the inner Oδ1 oxygen atoms of the catalytic aspartic acid residues. Comparison of the current XN structure with our previous XN structure of the wild-type HIV-1 protease-amprenavir complex suggests that the three mutations do not significantly alter the drug–enzyme interactions. This is in contrast to the observations in previous 100 K X-ray structures of these complexes that indicated loss of interactions by the drug with the triple mutant protease. These findings, thus, uncover limitations of structural analysis of drug binding using X-ray structures obtained at 100 K

Joint X‑ray/Neutron Crystallographic Study of HIV‑1 Protease with Clinical Inhibitor Amprenavir: Insights for Drug Design

HIV-1 protease is an important target for the development of antiviral inhibitors to treat AIDS. A room-temperature joint X-ray/neutron structure of the protease in complex with clinical drug amprenavir has been determined at 2.0 Å resolution. The structure provides direct determination of hydrogen atom positions in the enzyme active site. Analysis of the enzyme–drug interactions suggests that some hydrogen bonds may be weaker than deduced from the non-hydrogen interatomic distances. This information may be valuable for the design of improved protease inhibitors

Systematic and Controllable Negative, Zero, and Positive Thermal Expansion in Cubic Zr_1–<i>x</i>Sn_<i>x</i>Mo₂O₈

We describe the synthesis and characterization of a family of materials, Zr_1–<i>x</i>Sn_<i>x</i>Mo₂O₈ (0 < <i>x</i> < 1), whose isotropic thermal expansion coefficient can be systematically varied from negative to zero to positive values. These materials allow tunable expansion in a single phase as opposed to using a composite system. Linear thermal expansion coefficients, α_l, ranging from −7.9(2) × 10^–6 to +5.9(2) × 10^–6 K^–1 (12–500 K) can be achieved across the series; contraction and expansion limits are of the same order of magnitude as the expansion of typical ceramics. We also report the various structures and thermal expansion of “cubic” SnMo₂O₈, and we use time- and temperature-dependent diffraction studies to describe a series of phase transitions between different ordered and disordered states of this material