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

Abstract

Understanding the complex interactions of different building blocks within a sophisticated drug-delivery system (DDS), aimed at targeted transport of the drug to malignant cells, requires modeling techniques on different time and length scales. On the example of the anthracycline antibiotic doxorubicin (DOX), we investigate a potential DDS component, consisting of a gold nanoparticle and a short peptide sequence as carriers of DOX. The combination of atomistic molecular dynamics simulations and density functional theory calculations facilitates compiling a volcano plot, which allows deriving general conclusions on DDS constituents for chemotherapeutic agents within the class of anthracycline antibiotics: the nanoparticle and peptide carrier moieties need to be chosen in such a way that the anthracycline body of the drug is able to intercalate between both entities or between two (π-stacking) residues of the peptide. Using the popular volcano framework as a guideline, the present article connects the catalysis and biosimulation communities, thereby identifying a strategy to overcome the limiting volcano relation by tuning the coordination number of the drug in the DDS component.

A doxorubicin–peptide–gold nanoparticle conjugate as a functionalized drug delivery system: exploring the limits

“…This procedure is described in detail in our previous work. 9 The equilibration of the associate NP-DBP-2DOX is verified by the evolution of the total energy, temperature, pressure, and the root-mean-square deviation (RMSD) of the atomic coordinates of the highly flexible DBP with respect to the coordinates of the minimized structure (Fig. S2, ESI †).…”

“…12 For all Au atoms of the Au-NP, position restraints with a force constant of 1800 kJ mol À1 nm À2 are imposed during all MD simulations to prevent the Au-NP from dissociating, discussed in more detail in our previous work. 9,12 Berendsen barostat 19 and v-rescale thermostat 20 are employed to maintain conditions close to those in vivo, i.e., constant pressure of 1 bar and temperature of 310 K. During the simulations, all hydrogen-containing bonds are restrained by LINCS 21 or SETTLE 22 for the organic molecules and water, respectively. A Lennard-Jones potential with a cutoff of 1.2 nm and a switch function activated at 1.0 nm describes the non-bonded interactions, while electrostatics is assessed in the monopole approximation with the PME method, 23 applying a cutoff of 1.2 nm and a switch function turned on at 1.0 nm.…”

“…16 Parameters used for the charged forms of the drug and the DBP are specified in previous publications. 9,12 The parameters for the covalent Au–S junction between Au-NP and DBP as well as non-bonded parameters for Au are taken from the study of Giri and Spohr. 17 RESP charges 18 for the Au, C, S, and H atoms of the caps are given in our previous publication.…”

“…8 Their function may be understood even better if these conjugates are investigated by molecular modelling techniques on different time and length scales. 9 Computational studies on the anthracycline antibiotic doxorubicin 10 and DDS components 11 for its transport increased in recent years. In these contributions, the geometry of DOX in the gas phase and its structural and dynamic parameters in aqueous solution under ambient and physiological conditions were resolved, 10 or the interactions of DOX with a carrying unit were quantified by molecular simulations.…”

“…8 Their function may be understood even better if these conjugates are investigated by molecular modelling techniques on different time and length scales. 9…”