Role of Charge Density of Polycations in DNA Complexation and Condensation

Polycationic gene vectors have been studied extensively for gene delivery, and the charge density of polycations plays a pivotal role in condensing nucleic acids. Recently, we have synthesized two kinds of polycations with varied charge densities: poly(2-(dimethylamino)ethyl methacrylate) (denoted as A100) and a copolymer of 2-(tetramethyleneimino)ethyl methacrylate and 2-(diisopropyl-amino)ethyl methacrylate with a 3:1 feed ratio (denoted as B75D25). Despite its lower charge density, B75D25-based vectors exhibit higher transfection efficiency than A100-based vectors, prompting the hypothesis that hydrophobic interactions, rather than solely high charge density, enhance DNA complexation and gene delivery. This study aims to investigate the molecular mechanisms underlying these differences using molecular dynamics (MD) simulations to study the complexation of DNA with B75D25s and A100s. Our simulations reveal that DNA is quite uniformly covered by B75D25s, and the complexation is not only driven by the electrostatic attraction with DNA but more importantly by the hydrophobic interactions among B75D25s. In contrast, only a small fraction of A100s bind to DNA, which is due to the strong electrostatic repulsion among A100s. Our results reveal the contribution of hydrophobic interactions to the complexation of low-charge-density B75D25s with DNA. These results suggest that high charge density may not be essential for DNA condensation and efficient gene delivery.