modXNA: A Modular Approach to Parametrization of Modified Nucleic Acids for Use with Amber Force Fields

Area of Science:

• Biochemistry
• Computational Chemistry
• Drug Discovery

Background:

• Modified nucleic acids are crucial for developing novel therapeutics like RNA vaccines, antisense oligonucleotides, and aptamers.
• Accurate molecular modeling is essential for understanding the dynamic properties and stability of these modified nucleic acid systems.

Purpose of the Study:

• To present modXNA, a computational tool for generating modified nucleotides for Amber force fields.
• To streamline the parametrization process for molecular dynamics simulations of modified nucleic acids.

Main Methods:

• Development of modXNA for deriving modified nucleotides and building them for Amber simulations.
• Utilizing quantum mechanics for charge derivation and integrating modXNA into CPPTRAJ for simulation workflows.
• Validation using nucleic acid systems of varying sizes and modification complexities.

Main Results:

• modXNA successfully generates parameters for modified nucleotides, enabling accurate molecular dynamics simulations.
• Simulations using modXNA-derived parameters preserved the structural integrity and dynamics of modified nucleic acids.
• The tool facilitates efficient parametrization, reducing the computational burden.

Conclusions:

• modXNA is an effective tool for accelerating the design and development of modified nucleic acid therapeutics.
• The developed workflow enhances the capability of Amber simulations for noncanonical nucleic acid research.
• Accurate modeling of modified nucleic acids is vital for advancing drug discovery.