Multistep Drug Intercalation: Molecular Dynamics and Free Energy Studies of the Binding of Daunomycin to DNA

Abstract

Atomic-scale molecular dynamics and free energy calculations in explicit aqueous solvent are used to study the complex mechanism by which a molecule can intercalate between successive base pairs of the DNA double helix. We have analyzed the intercalation pathway for the anticancer drug daunomycin using two different methods: metadynamics and umbrella sampling. The resulting free energy pathways are found to be consistent with one another and point, within an equilibrium free energy context, to a three-step process. Daunomycin initially binds in the minor groove of DNA. An activated step then leads to rotation of the drug, coupled with DNA deformation that opens a wedge between the base pairs, bends DNA toward the major groove, and forms a metastable intermediate that resembles structures seen within the interfaces between DNA and minor-groove-binding proteins. Finally, crossing a small free energy barrier leads to further rotation of daunomycin and full intercalation of the drug, reestablishing stacking with the flanking base pairs and straightening the double helix.

Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration

“…(1) Small molecule conformational sampling [73][74][75][76]; (2) Protein-folding [77][78][79] and large-scale protein conformational sampling [80][81][82][83]; (3) Protein-protein/peptide-peptide interactions [84][85][86][87][88][89][90][91][92]; (4) DNA conformational changes [93] and DNA-DNA interactions [94][95][96]; (5) Binding and association free-energies [97][98][99][100][101][102][103][104][105][106][107]; (6) Adsorption on and permeation through lipid bilayers [108][109][110][111][112][113][114][115][116][117] …”

Molecular Origin of DNA Kinking by Transcription Factors

“…Also, the free energy profile is akin to what was observed for small molecule intercalation process. [25][26]30 However, unlike small molecule, intercalation of the AA in these DNA-AA systems results in the increase in free energy, due to hindrance from the backbone of AA. In case of the DNA-protein systems, both intercalation and deintercalation lead to an increase in the free energy indicating expectedly that the crystal structure is the most stable configuration.…”

Functionalized polythiophenes: Recognition materials for chemosensors and biosensors of superior sensitivity, selectivity, and detectability

“…However, other studies showed that the recognizing ssDNA could bind ions, proteins, and drugs as well [148,149]. Upon binding, a negatively charged recognizing oligonucleotide is often conformationally transformed.…”