Self-assembly of doxorubicin and a drug-binding peptide studied by molecular dynamics

A promising approach when developing efficient drug-delivery systems is to utilize a single carrier loaded with several drug molecules. Drug-binding peptides can be used as such transporters. However, knowledge about the microscopic mechanism of the self-assembly is needed. To unveil it, the behavior of a complex between an experimentally tailored drug-binding peptide (DBP) and the chemotherapeutic doxorubicin (DOX) is investigated via molecular dynamics. Simulations of one peptide and five DOX molecules in aqueous solution at room and body temperature are carried out. In all cases multiple DOXs bind spontaneously to the transporter, matching the expressed experimental affinity of the drug for the peptide. Aggregates form fast either stepwise, or by attaching preformed DOX associates. Tryptophan and tyrosine are key for the attachment, the dominant DBP-DOX interaction is pi-stacking. Considering this, DBP can be outlined as a prospective drug-carrying unit with enhanced potential for binding pi-conjugated drugs.