A Generalized Framework for Developing Dihedral Torsion Energy Terms in Nucleic Acids Force Fields

Area of Science:

• Biomolecular modeling
• Computational chemistry
• Structural biology

Background:

• Accurate force fields (FFs) are crucial for simulating large biomolecular systems.
• Existing nucleic acid FFs lack a universal framework for natural and modified variants across diverse environments.
• Developing robust FFs is essential for advancing oligonucleotide-based therapies.

Purpose of the Study:

• To introduce a general methodology for developing torsional energy parameters applicable to all nucleic acid systems.
• To create a force field (FF) generalizable to chemically modified nucleic acids.
• To achieve accurate conformational simulations of nucleic acids in physiological conditions.

Main Methods:

• Developed a general methodology for parametrizing key dihedral angles in nucleic acids.
• Simultaneously parametrized torsional energy parameters for nucleic acid systems.
• Validated the resulting force field, Creyon25, across various RNA and DNA structures.

Main Results:

• The Creyon25 force field demonstrates accuracy comparable to established AMBER and CHARMM models.
• The developed framework is generalizable to chemical modifications in nucleic acid linkers, sugars, and bases.
• The Creyon25 RNA model accurately reproduces experimentally observed structures; the DNA model shows potential for improvement.

Conclusions:

• This work represents a significant advancement in creating robust force fields for chemically modified nucleic acids.
• The Creyon25 FF supports the development and application of oligonucleotide therapies.
• The generalized methodology paves the way for future FF development for diverse nucleic acid systems.