# Developing a nucleic acid force field with direct chemical perception for computational modeling of nucleic acid therapeutics

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $74,284

## Abstract

PROJECT SUMMARY/ABSTRACT
Nucleic acid therapies provide a promising pathway for the treatment of diseases that are not amenable to target-
ing by traditional small molecule drugs. Reduction in toxicity and improvements in delivery and specificity have
been achieved through covalent modifications to naturally occurring RNAs, and these advances have recently led
to the regulatory approval of several nucleic acid therapies. For example, small interfering RNA (siRNA) silences
the expression of disease-causing messenger RNAs (mRNAs). However, this strategy can cause deleterious
silencing of off-target mRNAs with partial complementarity to the siRNA guide strand. A strategy for mitigation of
off-target silencing is destabilization of base pairing in one end of the duplex by substitution of the siRNA guide
strand by glycol nucleic acid (GNA), a nucleic acid analogue with an acyclic backbone. The precise mecha-
nisms of many covalent modifications, as well as their dependence on features such as sequence position and
structural motifs, are still poorly understood. Physics-based atomistic simulations can interrogate the impact of
these modifications on the conformational ensembles of nucleic acids and expedite the trial-and-error process for
molecules that are difficult to synthesize in the laboratory. The success of such simulations relies on the accuracy
of the force field, a parameterized function that uses classical physics to estimate potential energies from atomic
coordinates. A major obstacle to the application of physics-based simulations to therapeutic nucleic acids is the
difficulty in developing accurate force field parameters for covalently modified nucleotides. This proposal aims
to advance the role of simulations in the design and mechanistic understanding of therapeutic RNAs
with covalent modifications by developing an open source workflow to derive force field parameters and
run simulations of duplex hybridization for realistic therapeutic siRNAs. In Aim 1, a force field for nucleic
acids with arbitrary covalent modifications and backbone chemistry will be parameterized using a systematic and
reproducible workflow based on open source software infrastructure maintained by the Open Force Field Initia-
tive. In Aim 2, the force field parameters will be validated against experimental measurements of duplex melting
temperatures by performing melting simulations for RNA duplexes containing substitutions of GNA. In Aim 3,
the weighted ensemble enhanced sampling method will be applied to study the duplex association process for
guide siRNAs containing GNA substitutions pairing with target and off-target mRNAs. The proposed research will
enable reliable atomistic simulations of therapeutic RNAs, expanding the available toolkit for rational design of
such therapies. The systematic workflow for developing and validating nucleic acid force field parameters will be
easily generalizable to other covalent modifications beyond those in the siRNAs studied...

## Key facts

- **NIH application ID:** 10954247
- **Project number:** 5F32GM150240-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Chapin E Cavender
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,284
- **Award type:** 5
- **Project period:** 2023-09-15 → 2025-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10954247

## Citation

> US National Institutes of Health, RePORTER application 10954247, Developing a nucleic acid force field with direct chemical perception for computational modeling of nucleic acid therapeutics (5F32GM150240-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10954247. Licensed CC0.

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