Computer Simulation of New Terminally Charged Peptide Dendrimers with Neutral Spacers

In previous works, we carried out computer modeling of new positively charged molecules of complex topology and composition (peptide dendrimers based on lysine amino acid with AlaLys core, positively charged repeating units Lys2Lys ⁺ , Lys2Arg ⁺ , Lys2His ⁺ , and positively charged terminal residues (Lys ⁺² )). These dendrimers have very large positive charges distributed throughout all dendrimer volumes. They were designed to deliver oppositely charged drug molecules or/and genetic material into normal and cancer cells. The goal of the present work is to present new lysine-based peptide dendrimers with the same structure and topology but with strongly hydrophobic dipeptide spacers. In these molecules, only the surface of the dendrimers is charged, but their internal volume is hydrophobic. Such dendrimers can be used as nanocontainers with enhanced capability for the delivery of hydrophobic drug molecules. This work demonstrates that such dendrimers form fewer hydrogen bonds with water than the previously considered dendrimers with positively charged internal repeating units. An increase in internal hydrophobicity leads to compaction of the hydrophobic interior of the dendrimers. The temperature dependence of the size of the most hydrophobic dendrimer Lys2Leu has a minimum at a temperature of about T=300- 310K, which corresponds to the maximum hydrophobicity of leucine and isoleucine amino acid residues in globular proteins, obtained in a recently published study (van Dijk, 2015). The electrostatic properties of both dendrimers were also studied. It was shown that an increase in hydrophobicity leads to an increase of effective surface charge of the dendrimer and to increase of its zeta-potential due to a decrease in the penetration of counterions into its hydrophobic core. Results obtained here mean that these peptide dendrimers have a good perspective for future applications as carriers of small hydrophobic drug molecules.