A Molecular Dynamics Simulation of Complexes of Fullerenes and Lysine-Based Peptide Dendrimers with and without Glycine Spacers.

The development of new nanocontainers for hydrophobic drugs is one of the most important tasks of drug delivery. Dendrimers with hydrophobic interiors and soluble terminal groups have already been used as drug carriers. However, the most convenient candidates for this purpose are peptide dendrimers since their interiors could be modified by hydrophobic amino acid residues with a greater affinity for the transported molecules. The goal of this work is to perform the first molecular dynamics study of the complex formation of fullerenes C60 and C70 with Lys-2Gly, Lys G2, and Lys G3 peptide dendrimers in water. We carried out such simulations for six different systems and demonstrated that both fullerenes penetrate all these dendrimers and form stable complexes with them. The density and hydrophobicity inside the complex are greater than in dendrimers without fullerene, especially for complexes with Lys-2Gly dendrimers. It makes the internal regions of complexes less accessible to water and counterions and increases electrostatic and zeta potential compared to single dendrimers. The results for complexes based on Lys G2 and Lys G3 dendrimers are similar but less pronounced. Thus, all considered peptide dendrimers and especially the Lys-2Gly dendrimer could be used as nanocontainers for the delivery of fullerenes.

Hybrid Molecules Consisting of Lysine Dendrons with Several Hydrophobic Tails: A SCF Study of Self-Assembling.

In this article, we used the numerical self-consistent field method of Scheutjens-Fleer to study the micellization of hybrid molecules consisting of one polylysine dendron with charged end groups and several linear hydrophobic tails attached to its root. The main attention was paid to spherical micelles and the determination of the range of parameters at which they can appear. A relationship has been established between the size and internal structure of the resulting spherical micelles and the length and number of hydrophobic tails, as well as the number of dendron generations. It is shown that the splitting of the same number of hydrophobic monomers from one long tail into several short tails leads to a decrease in the aggregation number and, accordingly, the number of terminal charges in micelles. At the same time, it was shown that the surface area per dendron does not depend on the number of hydrophobic monomers or tails in the hybrid molecule. The relationship between the structure of hybrid molecules and the electrostatic properties of the resulting micelles has also been studied. It is found that the charge distribution in the corona depends on the number of dendron generations G in the hybrid molecule. For a small number of generations (up to G=3), a standard double electric layer is observed. For a larger number of generations (G=4), the charges of dendrons in the corona are divided into two populations: in the first population, the charges are in the spherical layer near the boundary between the micelle core and shell, and in the second population, the charges are near the periphery of the spherical shell. As a result, a part of the counterions is localized in the wide region between them. These results are of potential interest for the use of spherical dendromicelles as nanocontainers for drug delivery.

Implicit-Solvent Coarse-Grained Simulations of Linear-Dendritic Block Copolymer Micelles.

The design of nanoassemblies can be conveniently achieved by tuning the strength of the hydrophobic interactions of block copolymers in selective solvents. These block copolymer micelles form supramolecular aggregates, which have attracted great attention in the area of drug delivery and imaging in biomedicine due to their easy-to-tune properties and straightforward large-scale production. In the present work, we have investigated the micellization process of linear-dendritic block copolymers in order to elucidate the effect of branching on the micellar properties. We focus on block copolymers formed by linear hydrophobic blocks attached to either dendritic neutral or charged hydrophilic blocks. We have implemented a simple protocol for determining the equilibrium micellar size, which permits the study of linear-dendritic block copolymers in a wide range of block morphologies in an efficient and parallelizable manner. We have explored the impact of different topological and charge properties of the hydrophilic blocks on the equilibrium micellar properties and compared them to predictions from self-consistent field theory and scaling theory. We have found that, at higher degrees of branching in the corona and for short polymer chains, excluded volume interactions strongly influence the micellar aggregation as well as their effective charge.

Size and Structure of Empty and Filled Nanocontainer Based on Peptide Dendrimer with Histidine Spacers at Different pH.

Novel peptide dendrimer with Lys-2His repeating units was recently synthesized, studied by NMR (Molecules, 2019, 24, 2481) and tested as a nanocontainer for siRNA delivery (Int. J. Mol. Sci., 2020, 21, 3138). Histidine amino acid residues were inserted in the spacers of this dendrimer. Increase of their charge with a pH decrease turns a surface-charged dendrimer into a volume-charged one and should change all properties. In this paper, the molecular dynamics simulation method was applied to compare the properties of the dendrimer in water with explicit counterions at two different pHs (at normal pH with neutral histidines and at low pH with fully protonated histidines) in a wide interval of temperatures. We obtained that the dendrimer at low pH has essentially larger size and size fluctuations. The electrostatic properties of the dendrimers are different but they are in good agreement with the theoretical soft sphere model and practically do not depend on temperature. We have shown that the effect of pairing of side imidazole groups is much stronger in the dendrimer with neutral histidines than in the dendrimer with protonated histidines. We also demonstrated that the capacity of a nanocontainer based on this dendrimer with protonated histidines is significantly larger than that of a nanocontainer with neutral histidines.

Why the Orientational Mobility in Arginine and Lysine Spacers of Peptide Dendrimers Designed for Gene Delivery Is Different?

New peptide dendrimer with Lys-2Arg repeating units was recently studied experimentally by NMR (RSC Advances, 2019, 9, 18018) and tested as gene carrier successfully (Int. J. Mol. Sci., 2020, 21, 3138). The unusual slowing down of the orientational mobility of 2Arg spacers in this dendrimer was revealed. It has been suggested that this unexpected behavior is caused by the Arg-Arg pairing effect in water, which leads to entanglements between dendrimer branches. In this paper, we determine the reason for this slowing down using atomistic molecular dynamics simulation of this dendrimer. We present that the structural properties of Lys-2Arg dendrimer are close to those of the Lys-2Lys dendrimer at all temperatures (Polymers, 2020, 12, 1657). However, the orientational mobility of the H-H vector in CH2-N groups of 2Arg spacers in Lys-2Arg dendrimer is significantly slower than the mobility of the same vector in the Lys-2Lys dendrimer. This result is in agreement with the recent NMR experiments for the same systems. We revealed that this difference is not due to the arginine-arginine pairing, but is due to the semiflexibility effect associated with the different contour length from CH2-N group to the end of the side arginine or lysine segment in spacers.

Comparison of Structure and Local Dynamics of Two Peptide Dendrimers with the Same Backbone but with Different Side Groups in Their Spacers.

In this paper, we perform computer simulation of two lysine-based dendrimers with Lys-2Lys and Lys-2Gly repeating units. These dendrimers were recently studied experimentally by NMR (Sci. Reports, 2018, 8, 8916) and tested as carriers for gene delivery (Bioorg. Chem., 2020, 95, 103504). Simulation was performed by molecular dynamics method in a wide range of temperatures. We have shown that the Lys-2Lys dendrimer has a larger size but smaller fluctuations as well as lower internal density in comparison with the Lys-2Gly dendrimer. The Lys-2Lys dendrimer has larger charge but counterions form more ion pairs with its NH 3 + groups and reduce the bare charge and zeta potential of the first dendrimer more strongly. It was demonstrated that these differences between dendrimers are due to the lower flexibility and the larger charge (+2) of each 2Lys spacers in comparison with 2Gly ones. The terminal CH 2 groups in both dendrimers move faster than the inner CH 2 groups. The calculated temperature dependencies of the spin-lattice relaxation times of these groups for both dendrimers are in a good agreement with the experimental results obtained by NMR.