Stereochemical effects of non-ionic methylphosphonates on nucleotide conformations

Area of Science:

• Molecular Biology
• Organic Chemistry
• Biochemistry

Background:

• Nucleoside analogs are crucial in antiviral and anticancer therapies.
• Understanding their conformational properties is key to designing effective drugs.
• Methylphosphonates are a class of nucleoside analogs with potential therapeutic applications.

Purpose of the Study:

• To analyze the preferred conformations of deoxyribo- and ribonucleoside 3 -methylphosphonates.
• To compare these conformations with naturally occurring nucleoside 3 -phosphates.
• To investigate the impact of methylphosphonate substitution on the conformational stability of nucleic acid duplexes.

Main Methods:

• Minimization of conformational energy as a function of major parameters, including the sugar ring.
• Analysis of both S- and R-isomers of the methylphosphonate group.
• Computational modeling to predict conformational preferences and energy landscapes.

Main Results:

• Neither the substitution nor the diastereomer significantly altered preferred conformations compared to natural nucleoside 3 -phosphates.
• The chiral methylphosphonate group adopts a distal conformation relative to the C3 carbon.
• The S-isomer of methylphosphonate energetically disfavors the gauche conformation of the P-O3 bond, crucial for stacked helical duplexes.
• A high energy barrier between trans and gauche conformations was observed for the S-isomer.

Conclusions:

• Duplexes containing S-methylphosphonate may favor extended phosphodiester conformations.
• The observed conformational changes explain the lower melting temperatures of duplexes with S-methylphosphonate.
• Downfield shifts in 31P NMR signals of duplexes with S-methylphosphonate are attributed to these conformational effects.