Structure and conformation of pseudouridine analogues

Area of Science:

• Carbohydrate Chemistry
• Nucleic Acid Chemistry
• Structural Biology

Background:

• Pseudouridine is a modified nucleoside found in transfer RNA (tRNA).
• Understanding the conformational properties of pseudouridine is crucial for its biological function.
• The anomeric configuration and ring geometry influence nucleoside structure and interactions.

Purpose of the Study:

• To investigate the structural and conformational features of novel uracil analogues.
• To assess the applicability of these analogues as models for beta- and alpha-pseudouridine.
• To elucidate the solution-phase conformational dynamics and equilibrium of these compounds.

Main Methods:

• Synthesis of DL-trans- and DL-cis-5-(3-hydroxytetrahydrofuran-2-yl)uracils and related analogues.
• 270-MHz proton Nuclear Magnetic Resonance (NMR) spectroscopy for determining ring geometries.
• Computational analysis using two sets of calculations to model conformer populations and coupling constants.

Main Results:

• Cis analogues (4a, 4b) were identified as excellent conformational models for alpha-pseudouridine.
• Trans analogues (3a-c) exhibited an equilibrium favoring the N conformer (approx. 80%).
• This conformational preference in trans analogues differs significantly from the near-equal population of conformers in beta-pseudouridine.

Conclusions:

• The study provides insights into the conformational preferences of pseudouridine analogues.
• Conformational differences between cis and trans analogues impact their modeling capabilities for alpha- and beta-pseudouridine.
• These findings may have implications for understanding pseudouridine's pairing properties in tRNA.