Martini 3 Coarse-Grained Model of DNA for Heterogeneous Molecular Systems

Abstract

DNA often functions in heterogeneous molecular systems containing proteins, lipids, polymers, and other materials. All-atom molecular dynamics simulations can be used to study DNA in these multicomponent systems, but computational cost limits the accessible system sizes and time scales. Coarse-grained models extend these scales, but existing DNA models are generally not designed for interactions with a broad range of other molecular species. To fill this gap, we develop a coarse-grained model of DNA designed for use with the Martini 3 force field. The model was parameterized through an iterative Bayesian optimization workflow, which used a scaled Wasserstein metric to compare distributions of local geometrical features and global structure from coarse-grained simulations against all-atom reference simulations. The optimized model captures key structural and mechanical properties of single- and double-stranded DNA across varying strand lengths and ionic conditions, while retaining compatibility with the broader Martini 3 ecosystem. This compatibility enables DNA to be integrated with a broad range of molecular systems, as we illustrate through simulations of double-stranded DNA bound to a transcription factor, cholesterol-tagged DNA duplex interacting with a lipid bilayer, a crossover-containing DNA nanostructure, and single-stranded DNA adsorbing onto graphene. Together, these results establish a transferable coarse-grained model of DNA for simulations of heterogeneous biomolecular and engineered systems.