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

Bezrodnyi, Valeriy V; Shavykin, Oleg V.; Mikhtaniuk, Sofia E.; Neelov, Igor M.; Sheveleva, Nadezhda N.; Markelov, Denis A.

doi:10.3390/ijms21249749

Cited by 10 publications

(17 citation statements)

References 104 publications

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“…It is clear that the number of intra-dendrimer hydrogen bonds for the dendrimer with neutral and protonated histidines practically does not change with temperature. At the same time, the number of intermolecular hydrogen bonds of the dendrimer with water molecules decreases with temperature similarly to that for other peptide dendrimers studied by us earlier [40,41]. The stability of hydrogen bonds could be estimated from the lifetime of these hydrogen bonds [81][82][83].…”

Section: The Hydrogen Bondssupporting

confidence: 74%

“…The functions of ρ(r) for Lys-2His dendrimer is close to that of the Lys-2Gly dendrimer with similar neutral 2Gly spacers. For the Lys-2Hisp dendrimer with protonated 2Hisp spacers this function is close to that of the Lys-2Lys [40] and Lys-2Arg [41] dendrimers with similarly charged 2Lys and 2Arg spacers.…”

Section: The Spatial Symmetry and Atomic Distributionsmentioning

confidence: 63%

“…The authors suggested that the latter result was due to the effect of arginine-arginine pairing [51,52]. However, in our recent paper [41], it was shown that the pairing effect is small and this difference arises from the semi-flexibility effect associated with the different contour lengths from NMR active CH 2 -N groups to the end of lysine or arginine side chain in the spacers.…”

Section: Introductionmentioning

confidence: 80%

“…It was suggested that this is due to the arginine-arginine paring effect [51,52,84] previously studied for dimers and short arginine peptides. However, we have shown in our last paper that the pairing effect in the Lys-2Arg dendrimer is too small and another explanation of the slowdown was found [41]. In this paper, we focus on the possibility of pairing between imidazole groups [84] in the Lys-2His and Lys-2Hisp dendrimers and on comparing this with the guanidine pairing in the Lys-2Arg dendrimer obtained in our recent work.…”

Section: The Imidazole and Guanidine Pairingmentioning

confidence: 90%

“…The possibilities of using these dendrimers for siRNA delivery have been studied as well [38,39]. Molecular dynamic simulation has also been applied to some of these dendrimers [40,41]. It has been shown that dendrimers with neutral and charged dipeptide insertion (2Gly and 2Lys, correspondingly, having Lys-2Gly and Lys-2Lys repeating units) have different size and other properties.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: The Hydrogen Bondssupporting

confidence: 74%

Section: The Spatial Symmetry and Atomic Distributionsmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 80%

Section: The Imidazole and Guanidine Pairingmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Local Orientational Mobility of Collapsed Dendrimers

et al. 2021

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Dendrimers are regular hyperbranched macromolecules. The complex structure of the relaxation spectrum is one of the many features of dendrimers that does not fit into the classical concepts of polymers. The relaxation spectrum is manifested in various dynamic processes, including NMR relaxation. In this work, we study the collapsed and swollen dendrimers using NMR relaxation experiments and atomistic simulations of the modified lysine-based dendrimer with double histidine insertions (Lys-2His). This dendrimer is considered most suitable because the imidazole groups are not charged at a normal pH and become protonated at a low pH. We found that the orientational mobilities of segments and CH2 groups inside a collapsed dendrimer are opposite to those in the swollen conformation. Volume interactions suppress the internal local mobility, and reorientation occurs due to the rotation of the dendrimer as a whole. A comparison of the orientational mobility of the segments and CH2 groups for these conformations reveals that taking the segmental mobility into account gives an interpretation pitfall of the mobility of CH2 groups observed in NMR experiments. The studies of the Lys-2His dendrimers are of independent interest for biomedical research. However, our findings should be general for other collapsed dendrimer macromolecules.

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SAXS, DLS, and MD studies of the Rg/Rh ratio for swollen and collapsed dendrimers

Sheveleva,

Konarev,

Boyko

et al. 2024

The Journal of Chemical Physics

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The radius of gyration, Rg, and the hydrodynamic radius, Rh, are the main experimental parameters that characterize the size of linear and branched macromolecules. In the case of dendrimers in solution, the ratio Rg/Rh, depending on the global conformation, varies from 1 (for a Gaussian soft sphere) to 3/5 (for a hard sphere). However, for high-generation dendrimers, this ratio may be less than the limiting value for a hard sphere. To understand the reasons of the low Rg/Rh value (<0.77), we have studied the second-generation peptide dendrimer containing pH-sensitive histidine amino acid residues (Lys-2His dendrimer) using small-angle x-ray (SAXS) and dynamic light scattering (DLS) experiments, as well as molecular dynamics simulations. The Lys-2His dendrimer takes a swollen conformation at pH = 2 and a collapsed 1 at pH = 7. Our results show that the Rg/Rh ratio for the considered dendrimer decreases from ≈3/5 at pH = 2 to 0.5 at pH = 7. We have found that the very low Rg/Rh value is due to (1) the formation of a dense impenetrable core (i.e., the transformation of the dendrimer from a Gaussian soft sphere into a sphere with a dense core) and (2) the presence of a larger number of solvent molecules in the dendrimer corona than in a typical macromolecule. In addition, in this work, we have directly confirmed in the experiments for the first time, the collapse of the Lys-2His dendrimer with increasing pH.

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

Cited by 10 publications

References 104 publications

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

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

Local Orientational Mobility of Collapsed Dendrimers

SAXS, DLS, and MD studies of the Rg/Rh ratio for swollen and collapsed dendrimers

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