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 in 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. Molecular dynamics 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 density functional theory calculations. Principal component analysis 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 on the binding energy 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.

Method to Construct Volcano Relations by Multiscale Modeling: Building Bridges between the Catalysis and Biosimulation Communities

“…In case that one of the carriers is a biomolecule, such as a peptide employed in this work, it is indispensable that two π-stacking residues with a sufficient spatial distance are available, so that intercalation of the drug within the biomolecule becomes feasible. This confirms the conclusion from a previous study of one of the authors and extends it by showing that intercalation partners from different entities are operative. Assuming that the second carrier corresponds to a nanoparticle, such as the thiolate-protected Au-NP herein, particular attention should be paid to an appropriate surface modification of the NP.…”

“…The plot surprisingly reveals that the energy–distance dependence follows a type of volcano relation with a maximum at about d DOX‑NP = 1.95 nm and E stab = 7 kcal/mol. Our methodology ,, to assess the performance of a DDS component by the combination of MD simulations and DFT calculations is summarized in the SI, Section 4 (Figure S5). There, we also discuss how this approach can be adopted for the screening of electrocatalysts to advance the scientific discipline of electrocatalysis toward an inclusion of the electrolyte dynamics (Figure S6).…”

“…The peptide is attached to a methyl thiolate-protected Au-NP 36 by a covalent Au−S bond via the side chain of a cysteine residue. In the initial configuration, the drug is pre-adsorbed on a tryptophan entity (W5) of the DBP, corresponding to the most populated cluster of the complex DBP−DOX at 310 K in the previous study of Gocheva et al 32 The DBP has the following amino acid sequence: NH 3 + -CGGLWSPWYGGSW-CONH 2 and contains altogether three tryptophan residues at positions 5, 8, and 13. The NP−DBP−DOX complex is immersed in saline and simulated by atomistic MD in periodic boundary conditions.…”

“…DDSs may help overcoming undesirable side effects of the drug in vivo , such as cytotoxicity to undifferentiated cells, cardiotoxicity, and myelotoxicity, via targeted transport . The development of DDS components for anthracycline antibiotics is an active research field, in which various compositions, ranging from polymers, peptides, nanotubes, or gold nanoparticles, are suggested as potential building blocks. − Most of the DDS components that are investigated by means of model experiments or computer simulations in the literature comprise two building blocks only, that is, the drug and a carrier unit. Recently, we reported an advanced DDS component, consisting of three constituents .…”

“…Therein, the drug (DOX) is stabilized by a prototypical drug-binding peptide (DBP) and a gold nanoparticle (Au-NP) . The major advantages of this construct are as follows: (i) it has been demonstrated by Gocheva et al that, in the absence of the Au-NP, DOX is stacked by or intercalated in-between different tryptophan residues of the DBP and does not leave the surface of the peptide, thereby reaching an intermolecular interaction energy of the order of a weak covalent bond (up to 75 kcal/mol). , This is sufficient for the transport of the drug. (ii) Au-NPs have been shown to overcome multidrug resistance in cancer cells and, hence, are frequently applied for DOX delivery, mainly with a modified surface configuration to enhance their stability or add the targeting functionality. , Therefore, the combination of the DBP and the Au-NP as carrier moieties may unite the respective advantages in a more complex DDS component for DOX.…”