U.S. Department of Energy Office of Biological and Environmental Research

BER Research Highlights

Neutron Crystallography Shows How Drugs Bind to Enzymes
Published: August 28, 2012
Posted: December 04, 2012

more..." />
Complementarity of Neutron and X-Ray Data. Ball-and-stick figure of AZM and zinc (magenta sphere) in the HCA II active site. Heavier sulfur atoms (red) are clearly visible in the electron density map (blue; contoured at 2.0 s), while light deuterium atoms (cyan) are visible in the nuclear density map (yellow; contoured at 1.5 s).
Image credit: Los Alamos National Laboratory

X-ray crystallography is commonly used to determine how the atoms comprising a biological macromolecule are arranged. However, it has one serious limitation: it cannot observe directly where all of the hydrogen atoms are located, because they scatter x-rays very weakly (or in the case of H+, not at all). This underscores a major weakness of x-ray crystallography since an enzyme’s behavior usually depends on the arrangement of hydrogen atoms around its active site. In contrast, neutron crystallography can reveal the position of hydrogen atoms since they scatter neutrons as strongly as the other atoms found in proteins (i.e., C, N, O, and S). A recent study used neutron crystallography to show how carbonic anhydrase (HCA), an enzyme found in all life forms, binds acetazolamide (AZM), a carbonic anhydrase inhibitor drug clinically used to treat disorders ranging from glaucoma to epilepsy to altitude sickness. Experiments at the Protein Crystallography Station at Los Alamos National Laboratory (LANL) identified the hydrogen atoms at the binding site. The results clearly show the ionization state of AZM and how drug binding displaces key active site water molecules in HCA. It also revealed the hydrogen bonding interactions between the drug and the enzyme and showed the role of certain water molecules in drug binding. The experiments demonstrate that neutron beams provide crucial and specific information that will assist in applications such as structure-based drug design. The research was carried out by scientists at LANL and the University of Florida.

Reference: Fisher, S. Z., M. Aggarwal, A. Y. Kovalevsky, D. N. Silverman, and R. McKenna. 2012. “Neutron Diffraction of Acetazolamide-Bound Human Carbonic Anhydrase II Reveals Atomic Details of Drug Binding,” Journal of the American Chemical Society 134(36), 14726-729.  DOI: 10.1021/ja3068098. (Reference link).

Contact: Roland F. Hirsch, SC-23.2, (301) 903-9009
Topic Areas:

  • Research Area: Structural Biology, Biomolecular Characterization and Imaging
  • Research Area: Structural Biology Infrastructure

Division: SC-23.2 Biological Systems Science Division, BER


BER supports basic research and scientific user facilities to advance DOE missions in energy and environment. More about BER

Recent Highlights

May 10, 2019
Quantifying Decision Uncertainty in Water Management via a Coupled Agent-Based Model
Considering risk perception can improve the representation of human decision-making processes in age [more...]

May 09, 2019
Projecting Global Urban Area Growth Through 2100 Based on Historical Time Series Data and Future Scenarios
Study provides country-specific urban area growth models and the first dataset on country-level urba [more...]

May 05, 2019
Calibrating Building Energy Demand Models to Refine Long-Term Energy Planning
A new, flexible calibration approach improved model accuracy in capturing year-to-year changes in bu [more...]

May 03, 2019
Calibration and Uncertainty Analysis of Demeter for Better Downscaling of Global Land Use and Land Cover Projections
Researchers improved the Demeter model’s performance by calibrating key parameters and establi [more...]

Apr 22, 2019
Representation of U.S. Warm Temperature Extremes in Global Climate Model Ensembles
Representation of warm temperature events varies considerably among global climate models, which has [more...]

List all highlights (possible long download time)