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

Area of Science:

• Biomaterials Science
• Computational Chemistry
• Thrombosis Research

Background:

• Cancer-associated thrombosis necessitates anticoagulants with high bleeding risks.
• Cell-free DNA (cfDNA) activates the intrinsic coagulation pathway, contributing to thrombosis.
• Existing cationic polymers for cfDNA targeting exhibit cytotoxicity, demanding safer alternatives.

Purpose of the Study:

• To investigate the DNA binding of biocompatible polyamine-poly(ethylene glycol) (PEG) diblock polymers.
• To identify structural features essential for effective polymer-DNA binding and inhibition of DNA's procoagulant activity.
• To provide insights for designing novel antithrombotic agents.

Main Methods:

• All-atom molecular dynamics simulations were employed to analyze polymer-DNA interactions.
• Systematic examination of diblock polymers with varying cationic charge, PEG chain length, and conformations.
• Analysis of binding affinity, electrostatic interactions, and polymer structural changes upon DNA binding.

Main Results:

• Polymer-DNA binding is critically dependent on exposed cationic polyamine groups and sufficient electrostatic interactions.
• Intrachain associations between polyamine and PEG chains can lead to polymer self-collapse, hindering DNA binding.
• Strong hydrogen bonds and polyamine architecture influence polymer self-association and DNA binding efficacy.

Conclusions:

• Exposed cationic polyamine segments are essential for effective DNA binding by polyamine-PEG polymers.
• Minimizing polymer self-association through optimized structural design is key for potent antithrombotic activity.
• Findings guide the rational design of novel, biocompatible polymers for targeted antithrombotic therapy.