SPICA Force Field for Nucleic Acids and Its Application to Lipid Nanoparticles.

Nucleic acid therapies have emerged as promising treatments for various diseases associated with aberrant gene expression. Cationic lipid-nucleic acid complexes (lipoplexes) remain at the forefront of such therapeutic approaches as drug delivery carriers. To facilitate the study of these carriers through coarse-grained molecular dynamics (CG-MD) simulations, we extend our surface property fitting coarse-grained (SPICA) force field to develop a reliable DNA model with enhanced compatibility with lipids. In our DNA-CG model, the backbone is represented using three CG segments: the phosphate group is mapped to a single CG site, the deoxyribose to two CG sites, and nucleic bases are depicted as three- or four-atom rings. The bonded parameters were optimized to reproduce the mean and distribution of bond lengths, angles, and dihedrals obtained from all-atom (AA) MD simulations. Additionally, nonbonded parameters were fine-tuned to match experimental and AA-MD reference data, including the solvation free energy of nucleic bases, the free energy profile of base stacking interactions, and the transfer free energy of bases across different lipid bilayers. We also optimize the parameter of our CG model to reproduce the radius of gyration of single-stranded DNA obtained by AA-MD simulations. Further, by incorporating an elastic network to maintain the secondary structure of double-stranded DNA (dsDNA), we achieved a reasonable persistence length for dsDNA. Finally, we applied our DNA model to simulate lipoplexes, demonstrating its compatibility with lipids. The structural characteristics of these lipoplexes showed excellent agreement with experimental data, reinforcing the reliability of our model. Our model provides a solid foundation for large-scale simulations of complex DNA-lipid systems, such as lipid nanoparticles, in future studies.