This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Enzymes are often described as molecular machines that recognize and process specific molecules. However, they are not rigid structures.
Their shapes can change, affecting how molecules enter, interact with and remain within their active sites. Pyrimidine-nucleoside phosphorylase (PyNP) is an enzyme involved in the production of nucleic acid building blocks. It is relevant to the design of anticancer, antiviral and antibacterial drugs and can also be used to synthesize artificial nucleosides.
However, the molecular basis of how its changing shape affects molecular recognition has remained unclear. To investigate, a research team led by Professor Akihiko Hatano and researcher Kousei Takeshima of the Course of Chemistry and Biotechnology, Department of Materials Science and Chemistry, College of Engineering, Shibaura Institute of Technology, Japan, studied how different shapes of PyNP from Bacillus subtilis influence ligand retention and sugar preference. The team used all-atom molecular dynamics simulations across four conformational states, 13 structural probes and molecular dynamics trajectories totaling 15.6 microseconds of simulation time.
Their findings were published online in the journal ACS Omega. For years, researchers have used this enzyme to synthesize artificial nucleosides and have wondered why changing the sugar can alter the reaction. "We wanted to understand this question from the perspective of atomic-scale motions that experiments alone cannot reveal," Hatano said.
"This led us to examine how the enzyme and its bound molecules behave across different structural states." The researchers first examined how the enzyme's active-site pocket changes as the protein moves between different conformations. They found that the pocket expanded by approximately 1.4-fold between the most closed and most open states. The simulations then revealed a relationship between enzyme shape and ligand retention.
Across the simulations, 75.6% of trajectories in the closed group retained ligands in a bound state, compared with 55.1% in the open group, indicating that enzyme shape influences ligand retention. The researchers also found that ribose- and 2′-deoxyribose-containing compounds did not show a universal preference. Instead, sugar preference depended on both the individual compound and the enzyme's conformation.
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