Understanding enhanced mechanical stability of DNA in the presence of intercalated anticancer drug: Implications for DNA associated processes

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.

Theoretical insights into the effect of size and substitution patterns of azobenzene derivatives on the DNA G-quadruplex

“…The Parmbsc0 44 force field was selected for G-quadruplex nucleobases. Recent studies have reported that the Parmbsc0 is a valid force field for DNA simulations, [45][46][47] in particular for the simulations within the ns timescale. For atoms in the azobenzene, since it is a non-standard molecule, parameters were defined using the Generalized Amber Force Field (GAFF).…”

What do we know about DNA mechanics so far?

“…In contrast, once dsDNA makes a complex with the positively charged histone octamer that partially neutralizes DNA backbone charges, both its bending and stretch modulus increase by almost four times [17 ]. Sahoo et al recently discovered that when drug molecules bind to dsDNA in the intercalation mode, the stretch modulus increases drastically, whereas the persistence length decreases similar to the scenario of dsDNA in monovalent salt solutions [15 ]. However, there exist conflicting reports in the literature claiming no change in DNA persistence length upon drug intercalation, as discussed in Refs.…”

“…The design principle of a variety of drug molecules, including that for cancer and tumour treatments, is based on the principle that these molecules bind to DNA and make dsDNA melting extremely difficult, which thus could hamper the biological processes required for proper functioning of the cellular processes. In this context, Sahoo et al [15 ] employed steered molecular dynamics (MD) simulations of different pulling protocols to study the overstretching and melting transitions of dsDNA and found a significant increase in the dsDNA rupture force in the presence of intercalated drug molecules, which is due to the enhancement in the base-stacking interaction between adjacent base pairs present near to a drug intercalation site (Figure 3). This is in line with the recent revelation that the base-stacking interactions, instead of the previously thought base-pairing interactions, mostly contribute to the stability of dsDNA [59].…”

“…dsDNA has been studied in various conditions, such as unzipping, shearing, stretching, and under a torque, to mimic different biological scenarios [1]. These have provided increased insights to various interesting aspects of DNA such as emergence of S-DNA upon overstretching [5,10,51,52], modifications of DNA structural and mechanical properties under different environments such as drug intercalators [15 ], salts [17 ,46 ] and ionic liquids [26 ]. These information are the key inputs for DNA nanotechnological applications, enabling researchers to design various DNA nanostructures like DNA nanotubes [32,33 ] and DNA nanorobots for drug delivery [65], as well as in DNA nanoelectronics [51,52].…”

“…Moreover, the understanding of the mechanisms of the underlying DNA structural transitions has important implications for DNA-based nano-technological applications, such as rational drug design, programmable molecular machines, and DNA origami. Due to the advent of single-molecule manipulation techniques and theoretical/computational studies, significant progress has been made in understanding the structural, mechanical and elastic properties of DNA [1][2][3][4][5][6][7][8][9][10][11][12], as well as in understanding small-molecule interactions with DNA [13,14,15 ].…”