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Thermodynamic Dissection of the Intercalation Binding Process of Doxorubicin to dsDNA with Implications of Ionic and
Bahaa Jawad1,2, Lokendra Poudel3, Rudolf Podgornik4,5,6
1Department of Physics and Astronomy, University of Missouri-Kansas City, Kansas City 64110, Missouri, United States.
Abstract:
Doxorubicin (DOX) is a cancer drug that binds to dsDNA through intercalation. A comprehensive microsecond timescale molecular dynamics study is performed for DOX with 16 tetradecamer dsDNA sequences in explicit aqueous solvent, in order to investigate the intercalation process at both binding stages (conformational change and insertion binding stages). The molecular mechanics generalized Born surface area (MM-GBSA) method is adapted to quantify and break down the binding free energy (BFE) into its thermodynamic components, for a variety of different solution conditions as well as different DNA sequences. Our results show that the van der Waals interaction provides the largest contribution to the BFE at each stage of binding. The sequence selectivity depends mainly on the base pairs located downstream from the DOX intercalation site, with a preference for (AT)2 or (TA)2 driven by the favorable electrostatic and/or van der Waals interactions. Invoking the quartet sequence model proved to be most successful to predict the sequence selectivity. Our findings also indicate that the aqueous bathing solution (i.e., water and ions) opposes the formation of the DOX-DNA complex at every binding stage, thus implying that the complexation process preferably occurs at low ionic strength and is crucially dependent on solvent effects.
Insights
Doxorubicin (DOX) cancer drug intercalation into DNA is driven by van der Waals forces. Sequence selectivity favors AT or TA base pairs, and complex formation is hindered by aqueous solutions, suggesting low ionic strength is optimal.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Doxorubicin (DOX) is a widely used chemotherapy agent that exerts its effects by intercalating into double-stranded DNA (dsDNA).
- Understanding the molecular mechanisms and sequence preferences of DOX-DNA binding is crucial for optimizing cancer therapy and developing new drugs.
Purpose of the Study:
- To investigate the intercalation process of Doxorubicin into various dsDNA sequences using molecular dynamics simulations.
- To analyze the thermodynamic contributions to the binding free energy (BFE) and identify factors governing sequence selectivity.
Main Methods:
- Microsecond timescale molecular dynamics simulations of DOX with 16 different tetradecamer dsDNA sequences in explicit solvent.
- Application of the molecular mechanics generalized Born surface area (MM-GBSA) method to calculate and decompose the BFE.
Main Results:
- Van der Waals interactions were found to be the primary driver of BFE at all binding stages.
- DNA sequence selectivity was mainly influenced by base pairs downstream of the intercalation site, with a preference for (AT)2 or (TA)2 sequences.
- The quartet sequence model effectively predicted DOX-DNA binding selectivity.
Conclusions:
- The aqueous environment and ionic strength significantly impact DOX-DNA complex formation, opposing it at higher concentrations.
- Optimal DOX-DNA complexation is likely favored under low ionic strength conditions due to solvent effects.
