Understanding Enhanced Mechanical Stability of DNA in the Presence of Intercalated Anticancer Drug: Implications for DNA Associated Processes

TL;DR

This study uses molecular dynamics simulations to show that intercalated anticancer drugs significantly alter DNA's mechanical properties, increasing its stretch modulus and affecting its biological functions, which provides insight into their mechanism of action.

Contribution

It provides a detailed molecular-level understanding of how intercalated anticancer drugs modify DNA's mechanical properties, a novel insight into their functional mechanism.

Findings

Increase in DNA stretch modulus upon drug intercalation

Decrease in DNA persistence length and bending modulus

Higher forces required to stretch intercalated DNA

Abstract

Most of the anticancer drugs bind to double-stranded DNA (dsDNA) by intercalative-binding mode. Although experimental studies have become available recently, a molecular-level understanding of the interactions between the drug and dsDNA that lead to the stability of the intercalated drug is lacking. Of particular interest are the modifications of the mechanical properties of dsDNA observed in experiments. The latter could affect many biological functions, such as DNA transcription and replication. Here we probe, via all-atom molecular dynamics (MD) simulations, change in the mechanical properties of intercalated drug-DNA complexes for two intercalators, daunomycin and ethidium. We find that, upon drug intercalation, stretch modulus of DNA increases significantly, whereas its persistence length and bending modulus decrease. Steered MD simulations reveal that it requires higher forces to stretch the intercalated dsDNA complexes than the normal dsDNA. Adopting various pulling protocols to study force-induced DNA melting, we find that the dissociation of dsDNA becomes difficult in the presence of intercalators. The results obtained here provide a plausible mechanism of function of the anticancer drugs, i.e., via altering the mechanical properties of DNA. We also discuss long-time consequences of using these drugs, which require further in vivo investigations.