Neutron Crystallography Can Lead to Improved HIV Drugs

In a recent study, researchers were able to identify detailed interactions of hydrogen bonds at the active site of the enzyme HIV-1 protease, revealing a pH-inducing proton hopping mechanism that rules its behavior.

The researchers used neutron crystallography to make their discoveries, according to the study published by Angewandte Chemie.

HIV-1 protease transforms the virus particles into infectious HIV virions, which leads to AIDS. Without successful HIV-1 protease activity, the virions do not progress. Neuron crystallography has the ability to show hydrogen-bonding interactions that play a role in how a drug binds to its target.

The researchers used neuron crystallography to discover the structure of HIV-1 protease with Darunavir. Researchers analyzed neutron diffraction data to reveal properties of hydrogen-bonding interactions and also examined the enzyme’s catalytic activity changes with pH levels, according to the study.

Researchers found positions of hydrogen atoms before and after pH-induced 2-proton transfer between Darunavir and the enzyme. The proton transfer resulted in proton configuration that is crucial for catalytic activity.

"Darunavir's structure allows it to create more hydrogen bonds with the protease active site than most drugs of its type, while the backbone of HIV-1 protease maintains its spatial conformation in the presence of mutations," said researchers Andrey Kovalevsky, MS, PhD. "This means Darunavir-protease interaction is less likely to be disrupted by a mutation. Given these characteristics, Darunavir is an excellent therapy target to refine and therefore enhance HIV treatment."

Neutron crystallography has been crucial in providing details for hydrogen bonds that answer the questions about this HIV drug target.

"Moreover, we observed changes in hydrogen configurations induced by changes in protein surface charges at long distances," Dr Kovalevsky concluded. "This phenomenon may occur in other aspartic proteases, and perhaps in enzymes more generally."