Free energy calculation of modified base-pair formation in explicit solvent: A predictive model

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• RNA maturation involves post-transcriptional modifications.
• These modifications affect hydrogen bonding and base-pairing, including mismatch pairs.
• Understanding modified ribonucleoside base-pairing is key for RNA structure/function studies and design.

Purpose of the Study:

• To investigate the geometry and strength of base-pairing for modified ribonucleoside 5'-monophosphates.
• To determine the impact of modifications on RNA base-pairing and compare it to unmodified nucleosides.
• To explore the role of water molecules in mediating base-pair formation and stability.

Main Methods:

• Utilized AMBER force fields and molecular dynamics simulations (MDSs).
• Calculated geometry and free energies of base-pairings in aqueous solution under neutral conditions.
• Analyzed distances and energies of modified and unmodified base pairs.

Main Results:

• Unmodified uridines showed stable binding but with C1'-C1' distances shorter than A-form RNA.
• 5-oxyacetic acid uridine bound adenosine and guanosine comparably to unmodified uridine.
• 5-oxyacetic acid uridine formed A-form-like base pairs with uridine/cytidine when water mediated hydrogen bonding.

Conclusions:

• MDS accurately predicts the effects of RNA modifications on base-pairing.
• Water molecules play a significant role in mediating base-pair geometry and stability.
• Findings are critical for understanding native RNA structure, function, and designing novel RNA molecules.