NucleoPhi: A Transferable Force Field for Modified Nucleic Acids Enabling Atomistic Simulation–Driven Oligonucleotide Design

Accurate and transferable force fields are essential for reliably simulating both natural and chemically modified nucleic acids at atomistic resolution. However, there is no unified framework to consistently parameterize force fields across the wide range of sugar, base, and backbone or linker modifications commonly used in therapeutic oligonucleotides. Building on a generalized protocol, we develop force field parameters for the 2'-fluoro, 2'-O-methyl, and 2'FANA ribose modifications, as well as the pseudo-uridine nucleobase modification. These models were validated against a diverse set of experimentally determined structures and show good agreement with the observed conformational ensembles. We further demonstrate their utility in elucidating how chemical modifications modulate local structure, flexibility, and interaction energetics in nucleic acid hybrid duplexes, siRNA–Ago2 complexes, and the evasion of MC1 ribonuclease by pseudo-uridine. Overall, this work establishes a robust, generalizable pipeline for developing force fields for modified nucleic acids, enabling predictive atomistic simulations reliably.