Molecular Dynamics Simulations on Nucleic Acid Binding Polymers Designed To Arrest Thrombosis

Cancer-associated thrombosis is managed by the administration of anticoagulants and antithrombotic agents that have a high risk of inducing hemorrhagic complications. To develop safer strategies for antithrombotic therapy, in vivo activators of the intrinsic pathway, namely, cell-free nucleic acids (DNA and RNA) have been targeted with cationic, polyamine-based polymers. The cytotoxicity of the highly cationic polymers is a major drawback for their practical use, and biocompatible alternatives are in high demand. In this study, we carried out all-atom molecular dynamics simulations to systematically examine the DNA binding of polyamine-poly(ethylene glycol) (PEG) diblock polymers designed from biocompatible building blocks to inhibit the procoagulant activity of DNA. The differences in cationic charge, PEG chain length, and initial conformations of the polymers resulted in marked differences in their binding to DNA. We found that having an exposed cationic polyamine group is essential to polymer-DNA binding and a certain level of electrostatic interactions is necessary to maintain the bound state. Intrachain associations between the polyamine groups and PEG chains in some cases have led to a collapsed state of the polymer that precludes binding to DNA. This self-association is mainly due to a strong hydrogen bond between polymer polyamine and PEG groups and partly due to a partially charged semibranched polyamine group architecture. As polymer "masking" of DNA is thought to arrest DNA's prothrombotic activity, our findings highlight the desired structural features of the polymers for stronger DNA binding and provide insights into the design of novel antithrombotic agents.