Study of Complex of AEDG Tetrapeptide with KRH Dendrimer at Two
Different pH by Computer Simulation
SOFIA E. MIKHTANIUK1, EMIL I. FATULLAEV1,
IGOR M. NEELOV1,2,3,4, OLEG V. SHAVYKIN1,2,5
1Center of Chemical Engineering, ITMO University
2Department of Physics, St.Petersburg State University
3Peter the Great St.Petersburg Polytechnic University
4Department of Physics, Institute of Macromolecular Compounds
5Physics Department, Tver State University
St.Petersburg, 195277, Grazhdankii pr. 77-1
RUSSIA
Abstract: - In previous papers, we studied the behavior of lysine (Lys or K) based dendrimers of the second
generation with repeating units KKK and KRR (i.e., with branched neutral lysine and charged double lysine or
arginine (KK, RR) spacers). We also studied KLL, KAA, and KGG dendrimers with hydrophobic double
leucine, alanine, and glycine (LL, AA, GG) spacers and pH-dependent KHH dendrimers with double histidine
(HH) spacers. Their complexes with molecules of several medicinal peptides (including AEDG) were studied
as well. It was shown that lysine dendrimers with charged spacers are suitable for the delivery of oppositely
charged oligopeptides and genetic material, while dendrimers with hydrophobic internal spacers are good for
the delivery of hydrophobic oligopeptides and fullerenes. In the present paper, we study complexes of
molecules of AEDG peptide with KRH dendrimer containing arginine-histidine (RH) spacers. In this case, the
amino acid residues in the spacer (R and H) of dendrimer are different, and the charge of the H residue depends
on pH. We performed molecular dynamics simulations of the complexation of 16 AEDG molecules with a
dendrimer at two different pHs: a) KRH at pH>7 with fully uncharged histidines (H) and b) KRHp at pH<5
with fully protonated (Hp) histidines in aqueous solution with explicit counterions. It was found that the
dendrimer with protonated histidines forms a more compact complex. KRHp dendrimer can also carry more
AEDG tetrapeptide molecules than KRH.
Key-Words: - Peptide dendrimers, medicinal oligopeptides, complexes, molecular dynamics simulation
Received: March 24, 2024. Revised: Agust 19, 2024. Accepted: September 23, 2024. Published: November 11, 2024.
1 Introduction
Dendrimers are macromolecules with a regular
almost spherical tree-like structure originating from
a single root (core) and containing several spherical
layers [1]. The number of these layers between core
and terminal segments determines the number of
generations G. The uniqueness of dendrimers lies in
the fact that: (i) molecules of a given dendrimer
with a given number of generations G, synthesized
under the same conditions are practically
monodisperse; (ii) the number of branching points
and terminal groups of these molecules available
for functionalization increases very quickly with
increasing generation number G of the dendrimer,
[2]. Dendrimers can also have hydrophobic core or
carry a large electrical charge distributed throughout
the entire volume of the dendrimer or only over its
surface.
These properties determine the practical interest in
the use of dendrimers in industry [3] and
biomedicine [4]. Dendrimers can be used as
nanocontainers for the delivery of drugs [5] and
genetic material [6]. Dendrimers were applied in
medicine primarily for increase the solubility of
hydrophobic drugs, protect them during delivery,
and protect healthy cells from exposure to toxic
drugs. Application of poly(amidoamine) (PAMAM)
and polypropylene imine (PPI) for delivery of
genetic material was described in [7], for delivery
DNA in [8], and for delivery of siRNA using
PAMAM in [9] and using PAMAM and PPI in [10].
Recent study of new dendrimers of various structure
and their applications were described in [11],
synthesis, strucrture and functions of new
dendrimers with internal functionalization in [12]
and overview of different types of dendrimers in
[13]. Review of history and recent development of
MOLECULAR SCIENCES AND APPLICATIONS
DOI: 10.37394/232023.2024.4.11
Sofia E. Mikhtaniuk, Emil I. Fatullaev,
Igor M. Neelov, Oleg V. Shavykin
E-ISSN: 2732-9992
117
Volume 4, 2024
dendrimers for drug delivery in general were
discussed in [14], and in particular for drug delivery
to brain in [15]. Application of dendrimers for
general anticancer diagnostics and therapy was
described in [16], and specific of brain tumors
diagnostics and treatment in [17]. Dendrimers as
vectors for gene-directed enzyme prodrug therapy
was discussed in [18]. Synthesis and evaluation of
carbosilane dendrimers for siRNA delivery were
described in [19] and silencing of SARS-CoV-2
with siRNA-peptide dendrimer formulation in [20].
Peptide dendrimers based on natural monomers,
such as amino acid residues, are a good alternative
to synthetic dendrimers. The simplest ones are
lysine dendrimers consisting of only lysine
monomers [21]. The repeating unit of such a
dendrimer is a single branched lysine residue (Lys).
Experimental studies of the sizes of lysine
dendrimers of generation G=1-10 were carried out
in dimethylformamide [22] and in aqueous solutions
for G=3, [23] and for G=1-5, [24]. Dendrimers were
examined using molecular dynamics computer
simulations. The dependences of the sizes and other
structural and dynamic characteristics of these
dendrimers on the number of generations (G) were
studied for G=2-5, [25], G=1-6, [26], G=2, 4, [27],
G=1-5,[28] and G=1-5, [29]. In the last paper,
primary attention was paid to comparing lysine and
PAMAM dendrimers of the same generations. More
complicated peptide dendrimers containing lysine
octa-branched core and linear peptides consisting of
9-16 amino acids attached to their ends were
synthesized first in 1988 [30] for application as
multiple antigen peptides (MAPs). Synthesis of
similar dendrimers with 24-residue peptides
attached to dendrimer ends as described in [31].
Lysine dendrimers with one additional amino acid
between branching points were described in [24] for
G=1-5 and [32] for G=2. Dendrimers were also
described as having one or more other amino acid
residues attached to their ends. In particular,
dendrimers with arginine and histidine were studied
for applications in gene delivery and as
antibacterial, antiviral, and antiamiloid agents. In
particular, PAMAM dendrimers of generation G=4
with terminal lysine or terminal arginine were
studied in [33]. Arginine functionalized peptide
dendrimers of generations G=5 and G=6 were
investigated in [34]. Arginine-, lysine- and leucine-
bearing polyethyleneimine (PEI) dendrimers were
studied in [35]. Lysine dendrimers of generation
G=6 with lysine, arginine, and histidine ends were
used in [36]. PAMAM of generation G=4 with
arginine and histidine ends was studied in, [37].
Dendritic polyglycerolamine with arginine and
histidine end groups was investigated in [38].
Properties of different dendrimers with aminoacid
residues were compared in [39]. However, there was
practically no work on lysine dendrimers in which
other amino acid residues were inserted in the
internal generations of the dendrimer (except
papers, [24], for G=5 and [32], for G=2).
Recently, new types of lysine-based dendrimers in
which the internal part of the dendrimer was
functionalized. These dendrimers were successfully
synthesized and studied by the NMR method for
dendrimers with double glycine and double lysine
spacers, [40], double arginine spacers, [41] and
double histidine (with protonated and non-
protonated imidazole) spacers, [42]. The dendrimers
were also tested as a carrier for delivery of genetic
material with double glycine and double lysine
spacers [43] and double lysine, arginine, and
histidine spacers [44]. In this case, additional linear
spacers were inserted into the dendrimers between
all adjacent branch points. These spacers consisted
of double amino acid residues of lysine or glycine,
[40] and [43], arginine, [41] and [44], and
protonated histidine, [42] and [44]. The repeating
units in these dendrimers were Lys2Lys/Lys2Gly,
Lys2Arg, and Lys2His, correspondingly.
Peptide dendrimers based on second-generation
lysine dendrimers with spacers (2Lys or 2Gly, [45],
2Arg, [46], and 2His, [47]) inserted between their
branch points have also been studied using
computer modeling methods. However, there were
almost no studies of peptide dendrimers with
spacers containing two different aminoacids in the
internal generations of the dendrimer. In this article,
we close this gap. The insertion of such groups
should increase the capabilities of peptide
dendrimers for the transport of both hydrophobic
and hydrophilic drugs.
It is well known that many dendrimers are
amphiphilic. The inner region of the dendrimer is
usually more hydrophobic and can be used to
transport hydrophobic drug molecules. Improved
solubility of the dendrimer, as well as its complex
with hydrophobic drugs, is provided by hydrophilic
monomers, which are located at the periphery of the
dendrimer and are often positively charged. In our
recent papers, we also studied dendrimers with
double histidine spacers [48] and with histidine-
arginine/arginine-histidine spacers [49] which could
change their hydrophobicity with pH.
2 Problem Formulation
2.1 Formulation of the Problem
MOLECULAR SCIENCES AND APPLICATIONS
DOI: 10.37394/232023.2024.4.11
Sofia E. Mikhtaniuk, Emil I. Fatullaev,
Igor M. Neelov, Oleg V. Shavykin
E-ISSN: 2732-9992
118
Previously, we used lysine dendrimers with two
identical amino acid residues in each spacer
between dendrimer branch points. In this work, the
arginine residues (R) and histidine residue (H) are
different as in [49]. One of them (R) is charged at all
pH, the other (H) is uncharged at pH >7 and
positively charged at pH<5. It means that the
dendrimer as a whole is more charged as the pH
decreases.
2.2 Model and Method
In this work, we used an all-atom model of a peptide
dendrimer consisting of Lys-ArgHis (KRH) repeat
elements including Lys branch points and ArgHis
(RH) spacers between them. One KRH dendrimer
with neutral histidines (H) in spacers or one KRHp
dendrimer with protonated histidines (Hp) in spacers
and 16 molecules of the medical tetrapeptide Ala-
Glu-Asp-Gly (AEDG) were placed in a 9 nm
periodic cubic cell filled with water and counterions.
The simulation was carried out using the molecular
dynamics (MD) method with the AMBER99SB-
ILDN force field and the TIP3P water model in the
Gromacs package [50]. Before the start of the
simulation, the energy of individual subsystems was
minimized. Further minimization of the entire
system’s energy in an aqueous solution was done
before MD simulation. Electrostatic interactions
were calculated using the PME method. The
calculation of the main MD trajectory was carried
out in the NPT ensemble. The constant temperature
was ensured using a Nose-Hoover thermostat, and
constant pressure was maintained using a Parrinello-
Raman barostat. MD simulation was carried out for
500 ns.
3 Problem Solution
3.1 Process of Complex Formation
At the beginning of the MD simulation, the
dendrimer was located at the center of the periodic
cell, and 16 tetrapeptide molecules were located at
the periphery of this cell). Therefore, at the
beginning of the simulation, the distances between
the dendrimer and the peptide molecules were large.
To quantitatively describe the process of bringing
the dendrimer and peptides closer together due to
electrostatic interactions, the root-mean-square
distances d between the center of the dendrimer and
each of the 16 tetrapeptide molecules were
calculated (see Fig. 1). From this graph it is clear
that initial distance is between 4 and 5 nm. Then, it
constantly decreases during the first 40-50 ns of MD
simulation and reaches a plateau. This behavior
indicates the establishment of dynamic equilibrium
in the system, in which the root mean square
distance d between the dendrimer and peptide
molecules fluctuates but remains practically
unchanged.
Fig. 1 – Time dependences of distances d(t) between
the centers of the dendrimer and peptides in the
system for dendrimer with: a) neutral histidine
residues (H) in spacers, b) protonated histidine
residues (Hp) in spacers.
Fig. 2 - Dependences of the gyration radius Rg of
dendrimer and of subsystem containing dendrimer
and all peptides on time t for dendrimer with: a)
neutral histidine residues (H) in spacers, b)
protonated histidine residues (Hp) in spacers
Another characteristic demonstrating the formation
of the complex is the radius of inertia of the
subsystem consisting of a dendrimer and oppositely
MOLECULAR SCIENCES AND APPLICATIONS
DOI: 10.37394/232023.2024.4.11
Sofia E. Mikhtaniuk, Emil I. Fatullaev,
Igor M. Neelov, Oleg V. Shavykin
E-ISSN: 2732-9992
119
charged tetrapeptides (see Fig.2). A decrease in the
size of the subsystem consisting of dendrimer and
all peptides confirms the formation of a complex of
the dendrimer with peptides for both dendrimers
with uncharged (a) and with charged (b) histidines.
At the same time, the difference in the radii of the
complex and the dendrimer in Fig. 2a means that not
all peptides land on this dendrimer. In contrast, the
coincidence of Rg in Fig. 2b means that a more
charged dendrimer can hold almost all 16
tetrapeptides.
The number of hydrogen bonds between the
dendrimer and the peptides indicates how tightly the
peptides are bound to the dendrimer. From Fig. 3 it
follows that the average number of hydrogen bonds
at the beginning (before the peptides approach the
dendrimer) is zero. It quickly increases within 40-50
ns after the first contact of the dendrimer with the
peptide molecules. This value fluctuates
significantly over time, but its average value
practically does not change. The average number of
hydrogen bonds for a dendrimer with uncharged
histidines (Fig. 3a) is close to 62, and for a
dendrimer with protonated histidines (Fig. 3b)),
fluctuates around 76, which confirms a more
compact arrangement of the dendrimer and peptides
in the complex in the latter case.
Fig. 3. Dependences of hydrogen bonds number
nHB (t) between dendrimer and tetrapeptides on time
t for dendrimer with: a) neutral histidine residues
(H) in spacers, b) protonated histidine residues (Hp)
in spacers
To characterize the formation of the complex, we
used the radius of gyration of the subsystem
consisting of the dendrimer and all 16 peptides (see
Fig. 2). However, this value well reflects the process
of complex formation only if the dendrimer is
capable of retaining all the tetrapeptides present in
the system. A more accurate characteristic of the
instantaneous size of the complex is the radius of
gyration of the subsystem containing the dendrimer
and only those tetrapeptides associated with it at a
given time. The dependence of this value on time is
shown on Fig. 4.
Fig.4. Time dependences of the gyration radius
Rg(t) of complexes for dendrimer with: a) neutral
histidine residues (H) in spacers, b) protonated
histidine residues (Hp) in spacers
The most interesting value for a dendrimer-peptide
complex is the time dependence of the instantaneous
number of tetrapeptides n in the complex on time t
and its average value at long simulation times (after
reaching a plateau). This value is shown in Fig. 5.
Fig.5. Time dependences of number of peptides n(t)
in complexes: for dendrimer with: a) neutral
MOLECULAR SCIENCES AND APPLICATIONS
DOI: 10.37394/232023.2024.4.11
Sofia E. Mikhtaniuk, Emil I. Fatullaev,
Igor M. Neelov, Oleg V. Shavykin
E-ISSN: 2732-9992
120
histidine residues (H) in spacers, b) protonated
histidine residues (Hp) in spacers
The number of peptides in the complex is zero until
the first contact of one of the peptides with the
dendrimer. Then, it quickly grows to a maximum
value in the first 20 ns. After that, it reaches a
plateau and fluctuates around its average value of
approximately n=14 (Fig. 5a) for a dendrimer with
uncharged histidines and close to n=16 (Fig. 5b) for
a dendrimer with protonated histidines.
The results can be illustrated by snapshots of the
systems at the beginning and at the end of the
simulation (see Fig. 6). It is easy to see that two
tetrapeptides are out of complex for KRH dendrimer
at the end of simulation (Fig.6b) while for KRHp
dendrimer (Fig.6d) all 16 tetrapetides are in
complex at the end of trajectory.
(a)
(b)
(c)
(d)
Fig.6. The snapshots of the systems KRH+16AEDG
(a,b) and KRHp+16AEDG (c,d) at the start of
simulation, at time t = 0 ns (a, c) and at the end of it,
at t = 500 ns (b,d). Dendrimer atoms are shown as
spheres with a diameter equal to their van der Waals
radii while for tetrapeptides only main chains and
valence bonds of side chains are shown
3.2 Equilibrium Properties of the Complexes
After all the characteristics of both complexes reach
a plateau (approximately in the first 250 ns), any
equilibrium characteristics can be calculated by
averaging them over the second half (second 250 ns)
of the trajectory.
Fig. 7 shows the equilibrium distribution functions
of the distances between the center of mass of the
dendrimer and tetrapeptide molecules. It clearly
shows that complexes of tetrapeptides and a
dendrimer with uncharged histidines (KRH) are less
compact (the peak of the distribution g(d) for KRH
is located at larger distances d than for a dendrimer
with protonated histidines (KRHp)), and the width
of the first distribution is also larger than for KRHp.
Fig.7. Distribution function g(d) of distances d
between the centers of the dendrimer and peptides.
Fig. 8. The radial distribution function of dendrimer
atoms, atoms of peptides and for all atoms of
complex relatively center of mass of dendrimer for
dendrimer with: a) neutral histidine residues (H) in
spacers, b) protonated histidine residues (Hp) in
spacers
The radial distribution of the number of atoms of the
dendrimer, tetrapeptides, and all atoms in the system
relative to the center of mass of the dendrimer
provides the most complete information about the
internal structure of the complex. For a dendrimer
with uncharged histidines (Fig. 8a), the dendrimer
atoms make up the majority near its center of
inertia. Peptide atoms can penetrate the center of the
dendrimer, but their density there is small compared
to the density of the dendrimer in this place. The
MOLECULAR SCIENCES AND APPLICATIONS
DOI: 10.37394/232023.2024.4.11
Sofia E. Mikhtaniuk, Emil I. Fatullaev,
Igor M. Neelov, Oleg V. Shavykin
E-ISSN: 2732-9992
121
density of tetrapeptide atoms has maximum, located
at a distance of about 1.2 nm from the center of
mass of the dendrimer. For a dendrimer with
protonated histidines (Fig. 8b), tetrapeptide atoms,
on the contrary, penetrate deeply into the dendrimer
and make up the majority near the center of mass (at
r=0). In contrast, dendrimer atoms are displaced
from the center and have a maximum density at a
distance of about r = 0.6 nm from the center of mass
of the protonated dendrimer.
Average values obtained during second part of
trajectory are presented in Table 1. The avegage
distances <d> between the centers of dendrimers
and peptides and the size of complex are smaller for
dendrimer with protonated dendrimer (KRHp), The
number of hydrogen bonds between dendrimers and
peptides and the number of peptides in complexes
are greater for dendrimer with protonated histidines
(KRHp).
Table 1. The average values: average distances <d>
between dendrimer center and peptide molecule,
number of hydrogen bonds <NHb> between them,
number of peptide molecules in the complex <Nlc>.
System
<d>
<nHb>
<Nlc>
KRH+16AEDG
2,36
61,7
14,0
KRHp+16AEDG
1,85
76,6
15,6
These average values are in good agreement with
results obtained in parts 3.1 and 3.2 of the paper.
4 Conclusion
In the present paper, we studied the complexes of
molecules of AEDG peptide with dendrimers
containing arginine-histidine (RH) spacers with
charge of histidines depending on pH value. We
performed molecular dynamics simulations of the
complexation of 16 AEDG molecules with a
dendrimer at two different pHs: a) pH>7 with fully
uncharged histidines (H) and b) pH<5 with fully
protonated (Hp) histidines in aqueous solution with
explicit counterions. It was found that the dendrimer
with protonated histidines forms a more compact
complex containing a larger number of AEDG
tetrapeptide molecules.
References:
[1] Buhleier, E.; Wehner, E.; Vogtle, F. "Cascade"
and "nonskid-chain-like" syntheses of molecular
cavity topologies. Synthesis 1978, 78, 155–158.
[2] Frechet, M.J.; Tomalia, D.A., Eds. Dendrimers
and other Dendritic polymer, 1 ed.; Wiley: England,
2001. doi:10.1002/0470845821.
[3] Patel, H.N.; Patel, P.M. Dendrimer applications -
a review. Int J Pharm Bio Sci, 2013, 4, 454–463.
[4] Abbasi, E.; Aval, S.; Akbarzadeh, A.; et al.
Dendrimers: synthesis, applications, and properties.
Nanoscale Research Letters, 2014, 9, 247.
[5] Madaan, K.; Kumar, S.; Poonia, N.; et al.
Dendrimers in drug delivery and targeting: Drug-
dendrimer interactions and toxicity issues. J Pharm
Bioallied Sci. 2014, 6, 139–150..
[6] Sherje, A.P.; Jadhav, M.; Dravyakar, B.R.; et al.
Dendrimers: A versatile nanocarrier for drug
delivery and targeting. Int J Pharm. 2018, 548, 707–
720.
[7] Rabiee, N.; Ahmadvand, S.; Ahmadi, S.; et al.
Carbosilane Dendrimers: Drug and Gene Delivery
Applications. Journal of Drug Delivery Science and
Technology 2020, p. 101879.
[8] Dufes, C.; Uchegbu, I.; Schatzlein, A.G.
Dendrimers in gene delivery. Adv. Drug Delivery
Rev. 2005, 57, 2177–2202.
[9] Zhou, J.; Wu, J.; Hafdi, N.; et al. PAMAM
dendrimers for efficient siRNA delivery and potent
gene silencing. Chem. Commun. 2006, 22, 2362–
2364.
[10] Biswas, S.; Torchilin, V. Dendrimers for
siRNA delivery. Pharmaceuticals 2013, 6, 161–183.
[11] Pérez-Ferreiro, M.; Abelairas, A.; Criado, A.;
et al. Dendrimers: Exploring Their Wide Structural
Variety and Applications. Polymers 2023, 15, 4369.
[12]Smith R.J., Gorman C., Menegatti S. Synthesis,
structure, and function of internally functionalized
dendrimers, J Polym Sci. 2021, 59:10–28.
[13] Sarode R.J., Mahajan H.S. Dendrimers for drug
delivery: An overview of its classes, synthesis, and
applications, 2024, 98, 105896
[14] Wang, J., Li, B., Qiu, L. et al. Dendrimer-based
drug delivery systems: history, challenges, and latest
developments. J. Biol. Eng., 2022, 16, 18.
[15] Zhu Y., Liu C., Pang Z. Dendrimer-Based Drug
Delivery Systems for Brain Targeting, Biomolecules
2019, 9, 790.
[16] Bober, Z.;Bartusik-Aebisher, D.; Aebisher, D.
Application of Dendrimers in Anticancer
Diagnostics and Therapy. Molecules, 2022, 27,
3237.
[17] Kaurav M., Ruhi S., Al-Goshae H.A. et al
Dendrimer: An update on recent developments and
future opportunities for the brain tumors diagnosis
treatment, Front. Pharmacol., 2023, 14
[18] Chis, A.A.; Dobrea, C.M.; Rus, L.-L. et al
Dendrimers as Non-Viral Vectors in Gene-Directed
MOLECULAR SCIENCES AND APPLICATIONS
DOI: 10.37394/232023.2024.4.11
Sofia E. Mikhtaniuk, Emil I. Fatullaev,
Igor M. Neelov, Oleg V. Shavykin
E-ISSN: 2732-9992
122
Enzyme Prodrug Therapy. Molecules 2021, 26,
5976.
[19] Zawadzki S., Martín‑Serrano A., Okła E. et al,
Synthesis and biophysical evaluation of carbosilane
dendrimers as therapeutic siRNA Carriers, Scientifc
Reports, 2024, 14, 1615.
[20] Khaitov M., Nikonova A., Shilovskiy I. et al.
Silencing of SARS-CoV-2 with modified siRNA-
peptide dendrimer formulation, Allergy. 2021; 76,
2840-2854.
[21] Denkewalter, R.G.; Kolc, J.; Lukasavage, W.J.
Macromolecular Highly Branched Homogeneous
Compound Based on Lysine Units. United States
Patent, US4289872A, 1981.
[22] Aharoni, S.M.; Crosby III, C.R.; Walsh, E.K.
Size and solution properties of globular tert-
butyloxycarbonyl-poly(α,ϵ-L-lysine).
Macromolecules 1982, 15, 1093–1098.
[23] Vlasov, G. et al. Lysine Dendrimers and Their
Starburst Polymer Derivatives: Possible Application
for DNA Compaction and in vitro Delivery of
Genetic Constructs. Russian Journal of Bioorganic
Chemistry 2004, 30, 15–24.
[24] Vlasov, G.; at al Dendrimers Based on a-
Amino Acids: Synthesis and Hydrodynamic
Characteristics. Doklady Physical Chemistry 2004,
399, 366–368.
[25] Markelov, D.A.; Falkovich, S.G. Ilyash, at al.
Molecular dynamics simulation of spin–lattice
NMR relaxation in poly-l-lysine dendrimers: a
manifestation of the semiflexibility effect. Phys.
Chem. Chem. Phys. 2015, 17, 3214–3226.
[26] Roberts, B.P.; Scanlon, M.J.; Krippner, G.Y.;
Chalmers, D.K. Molecular Dynamics of Poly(l-
lysine) Dendrimers with Naphthalene Disulfonate
Caps. Macromolecules 2009, 42, 2775–2783.
[27] Neelov, I.; Markelov, D.; Falkovich et al S.;
Mathematical simulation of lysine dendrimers.
Temperature dependencies. Polymer Science, Ser. C
2013, 55, 154–161.
[28] Neelov, I.; Falkovich, S.; Markelov, D.; et al
Dendrimer in Biological Applications, London,
RSC, 2013, 99–114.
[29] Darinskii A.A., Gotlib, Y.Y., Lyulin, A.V. et
al. Vysokomolek. Soed., Computer simulation of
local dynamics of a polymer chain in the orienting
field of the LC type, 1991, Vysokomolekularnye
Soedineniya. Seriya А 33, 1211-1220.
[30] Tam, J. Synthetic peptide vaccine design:
Synthesis and properties of a high-density multiple
antigenic peptide system. Proc. Natl.Acad. Sci. USA
1988, 85, 5409–5413.
[31] Rao, C.; Tam, J. Synthesis of peptide
dendrimer. J. Am. Chem. Soc. 1994, 116, 6975–
6976
[32] Darbre, T.; Reymond, J.L. Peptide dendrimers
as artificial enzymes, receptors, and drug-delivery
agents. Acc. Chem. Res. 2006, 39, 925–934.
[33] Choi, J.S.; Nam, K.; Park, J.y.; Kim, J.B.; Lee,
J.K.; Park, J.S. Enhanced Transfection Efficiency of
PAMAM Dendrimer by Surface Modification with
L-Arginine. J. Control. Release 2004, 99, 445-456.
[34] Luo, K.; Li, C.; Li, L.; She, W.; Wang, G.; Gu,
Z. Arginine functionalized peptide dendrimers as
potential gene delivery vehicles. Biomaterials 2012,
33, 4917-4927.
[35] Aldawsari, H.; Raj, B.S.; Edrada-Ebel, R.;
Blatchford, D.R.; Tate, R.J.; Tetley, L.; Dufès, C.
Enhanced gene expression in tumors after
intravenous administration of arginine-, lysine- and
leucine-bearing polyethylenimine polyplex.
Nanomed. Nanotechnol. Biol. Med. 2011, 7, 615–
623.
[36] Okuda, T.; Sugiyama, A.; Niidome, T.; Aoyagi,
H. Characters of dendritic poly(L-Arhlysine)
analogs with the terminal lysines replaced with
arginines and histidines as gene carriers in vitro.
Biomaterials 2004,49925, 537–544.
[37] Lee, H.; Choi, J.S. Larson R.G. Molecular
Dynamics Studies of the Size and Internal Structure
of the PAMAM Dendrimer Grafted with Arginine
and Histidine. Macromolecules 2011, 44, 8681–
8686
[38] Sheikhi Mehrabadi, F.; Zeng, H.; Johnson, M.;
Schlesener, C.; Guan, Z.; Haag, R. Multivalent
dendritic polyglycerolamine with arginine and
histidine end groups for efficient siRNA
transfection. Beilstein J. Org. Chem. 2015, 11, 763–
772.
[39] Santos, A.; Veiga, F.; Figueiras, A. Dendrimers
as Pharmaceutical Excipients: Synthesis, Properties,
Toxicity, and Biomedical Applications. Materials
2020, 13, 65.
[40] Sheveleva, N.N.; Markelov, D.A.; Vovk, M.A.;
et al. NMR studies of excluded volume interactions
in peptide dendrimers. Scientific Reports 2018, 8,
8916.
[41] Sheveleva, N.N.; Markelov, D.A.; Vovk, M.A.
et al. Lysine-based dendrimer with double arginine
residues. RSC Advances 2019, 9, 18018–18026.
[42] Sheveleva, N.N.; Markelov, D.A.; Vovk et al
Stable Deuterium Labeling of Histidine-Rich
Lysine-Based Dendrimers. Molecules 2019, 24,
2481
[43] Gorzkiewicz, M.; Konopka, M.; Janaszewska,
at al. Application of new lysine-based peptide
dendrimers D3K2 and D3G2 for gene delivery:
Specific cytotoxicity to cancer cells and transfection
in vitro. Bioorg. Chem. 2020, 95, 103504.
MOLECULAR SCIENCES AND APPLICATIONS
DOI: 10.37394/232023.2024.4.11
Sofia E. Mikhtaniuk, Emil I. Fatullaev,
Igor M. Neelov, Oleg V. Shavykin
E-ISSN: 2732-9992
123
[44] Gorzkiewicz, M.; Kopec, O.; Janaszewska, et
al. Poly(lysine) Dendrimers Form Complexes with
siRNA and Provide Its Efficient Uptake by Myeloid
Cells: Model Studies for Therapeutic Nucleic Acid
Delivery. Int. J. Mol. Sci. 2020, 21, 3138.
[45] Mikhtaniuk, S.E.; Bezrodnyi, V.V.; Shavykin
O.V. et al. Comparison of Structure and Local
Dynamics of Two Peptide Dendrimers with the
Same Backbone but with Different Side Groups in
Their Spacers. Polymers 2020, 12, 1657.
[46] Bezrodnyi, V.V.; Shavykin, O.V.; Mikhtaniuk,
S.E. et al. Why the orientational mobility in arginine
and lysine spacers of peptide dendrimers designed
for gene delivery is different? Int. J. Mol. Sci. 2020,
21, 9749.
[47] Bezrodnyi, V.V.; Mikhtaniuk, S. E.; Shavykin,
O. V.; et al. Size and Structure of Empty and Filled
Nanocontainer Based on Peptide Dendrimer with
Histidine Spacers at Different pH, Molecules 2021,
26, 6552.
[48] Sheveleva et al. Local Orientational Mobility of
Collapsed Dendrimers, Macromolecules, 2021, 54,
11083-11092.
[49] Sheveleva, N.N.; Tarasenko, I.I.; Vovk, M.A.;
et al. NMR Studies of Two Lysine Based
Dendrimers with Insertion of Similar Histidine-
Arginine and Arginine-Histidine Spacers Having
Different Properties for Application in Drug
Delivery. Int. J. Mol. Sci. 2023, 24, 19.
[50] Abraham M.J., Murtola T., Schulz R. et al.
GROMACS: High Performance Molecular
Simulations through Multi-Level Parallelism from
Laptops to Supercomputers. SoftwareX, 2015, 1–2,
19–25.
Contribution of Individual Authors to the
Creation of a Scientific Article (Ghostwriting
Policy)
Sofia Mikhtaniuk, Igor Neelov and Oleg Shavykin
formulated the problem for modeling. Sofia
Mikhtaniuk, Emil Fatullaev prepared initial
conformations of molecules for simulation. and
carried out the simulation. Sofia Mikhtaniuk and
Oleg Shavykin prepared plots, and wrote intials text.
Sofia Mikhtaniuk, Igor Neelov and Oleg Shavykin
prepared final manuscript and formulated
conclusion.
Sources of Funding for Research Presented in a
Scientific Article or Scientific Article Itself
This work was supported by RSF(grant No. 23-13-
00144) and St.-Petersburg State University research
project 116446059
MOLECULAR SCIENCES AND APPLICATIONS
DOI: 10.37394/232023.2024.4.11
Sofia E. Mikhtaniuk, Emil I. Fatullaev,
Igor M. Neelov, Oleg V. Shavykin
E-ISSN: 2732-9992
124
Conflict of Interest
The authors have no conflicts of interest to declare
that are relevant to the content of this article.
Creative Commons Attribution License 4.0
(Attribution 4.0 International, CC BY 4.0)
This article is published under the terms of the
Creative Commons Attribution License 4.0
https://creativecommons.org/licenses/by/4.0/deed.en
_US