Characterization of the interaction forces in a drug carrier complex of doxorubicin with a drug-binding peptide

Abstract

Polypeptide-based materials are used as building blocks for drug delivery systems aimed at toxicity decrease of chemotherapeutics. A molecular-level approach is adopted for investigating the non-covalent interactions between doxorubicin and a recently synthesized drug-binging peptide as a key part of a system for delivery to neoplastic cells. MD simulations in aqueous solution at room and body temperature are applied to investigate the structure and the binding modes within the drug-peptide complex. The tryptophans are outlined as the main chemotherapeutic adsorption sites and the importance of their placement in the peptide sequence is highlighted. The drug-peptide binging energy is evaluated by DFT calculations. PCA reveals comparable importance of several types of interaction for the binding strength. π-Stacking is dominant but other factors are also significant: intercalation, peptide backbone stacking, electrostatics, dispersion, and solvation. Intra- and intermolecular H-bonding also stabilizes the complexes. The influence of solvent molecules is mild. The obtained data characterize the drug-to-peptide attachment as a mainly attractive collective process with interactions spanning a broad range of values. These results explain with atomistic detail the experimentally registered doxorubicin-binging ability of the peptide and outline the complex as a prospective carrying unit that can be employed in design of drug-delivery systems.

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The study reports the results from molecular modeling of a hydrated drug-peptide complex, in which a chemotherapeutic is non-covalently adsorbed onto a drug-binding peptide. The probable structures of the complex are identified and thoroughly characterized. The feasible peptide adsorption sites and patterns of the drug association are outlined and an essential structural factor for strong binding is suggested. The forces that keep the molecule of the pharmaceutic attached to the carrier surface are elucidated and their relative importance is quantified.

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