  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.
