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Lukasz Konczak,1 Jolanta Narkiewicz-Michalek,2 Giorgia Pastorin,3 Tomasz Panczyk1 1Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Cracow, 2Department of Chemistry, Maria Curie-Sklodowska University, Lublin, Poland; 3Department of Pharmacy, National University of Singapore, Singapore Abstract: This work deals with the role of intermolecular interactions in the stability of a carbon nanotube (CNT) capped by functionalized gold nanoparticles (AuNPs). The importance of such a system is due to its potential application as a pH-controlled drug carrier. Our preliminary experimental studies showed that fabrication of such a nanobottle/nanocontainer is feasible and it is possible to encapsulate the anticancer drug cisplatin inside the inner space of a CNT and seal its ends by functionalized AuNPs. The expected behavior, that is, detachment of AuNPs at acidic pH and the release of cisplatin, was, however, not observed. On the other hand, our theoretical studies of chemically identical system led to the conclusion that the release of cisplatin at acidic pH should be observed. Therefore, in this work, a deeper theoretical analysis of various factors that could be responsible for the disagreement between experimental and theoretical results were performed. The study found that the major factor is a large dispersion interaction component acting between CNT and AuNP in solution in the case of the experimental system. This factor can be controlled to some extent by tuning the system size or the ratio between AuNP diameter and CNT diameter. Thus, such kind of a pH-sensitive drug carrier is still of great interest, but its structural parameters need to be properly adjusted. Keywords: hydrazone bond, drug delivery, dispersion interactions, cisplatin, acidic pH

Jian Li,1 Sia Lee Yoong,2 Wei Jiang Goh,2 Bertrand Czarny,1 Zhi Yang,1 Kingshuk Poddar,2,3 Michal M Dykas,2,3 Abhijeet Patra,2,3 T Venkatesan,2,3 Tomasz Panczyk,4 Chengkuo Lee,5 Giorgia Pastorin1–3 1Department of Pharmacy, National University of Singapore, 2NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences (CeLS), 3NUSNNI-NanoCore, National University of Singapore, Singapore; 4Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Cracow, Poland; 5Department of Electrical and Computer Engineering, National University of Singapore, Singapore Abstract: Carbon nanotubes’ (CNTs) hollow interior space has been explored for biomedical applications, such as drug repository against undesirable inactivation. To further devise CNTs as smart material for controlled release of cargo molecules, we propose the concept of “gold-carbon nanobottles”. After encapsulating cis-diammineplatinum(II) dichloride (cisplatin, CDDP) in CNTs, we covalently attached gold nanoparticles (AuNPs) at the open-tips of CNTs via different cleavable linkages, namely hydrazine, ester, and disulfide-containing linkages. Compared with our previous study in which more than 80% of CDDP leaked from CNTs in 2 hours, AuNPs were found to significantly decrease such spontaneous release to

Poly(amidoamine) dendrimer (PAMAM)/carbon quantum dot (CQD) nanohybrids are promising candidates for many biomedical applications, including drug delivery. Effectively designing a hybrid nanocarrier requires a deep understanding of the interactions of the hybrid nanoparticle with the drug to ensure drug stability and therapeutic efficiency. In this study, we utilized fully atomistic molecular dynamics (MD) simulations to investigate the adsorption behavior of a doxorubicin (DOX) anticancer drug onto a zwitterion/PAMAM/CQD hybrid nanocarrier. The hybrid nanoparticles were composed of CQD, at two oxidation levels, grafted with PAMAM dendrimers of generation 3 (G3) or 4 (G4) decorated with zwitterion monomers. Our work reveals that the generation of the grafted dendrimer was the primary determinant of efficient adsorption of DOX, unlike the oxidation level of CQD or dendrimer surface chemistry. After grafting, the G4 dendrimers assume a more stretched conformation compared to the G3 dendrimers. This allowed DOX molecules to penetrate inside the dendritic cavities of G4 dendrimers, resulting in enhanced drug protection. The hydrophobic interaction, between the aromatic structure of DOX molecules and the nonpolar parts of dendrimers, has been proven to play a crucial role in mediating the adsorption of drug molecules. These findings provide valuable insights to assist in the design of a zwitterion/PAMAM/CQD hybrid nanoplatform for drug delivery applications.

Polypropylene (PP) and polystyrene (PS) underwent a comprehensive investigation into their mechanical and chemical degradation through reactive molecular dynamics simulations. The simulations utilized the ReaxFF force field for CHO (carbon-hydrogen-oxygen) systems in the combustion branch. The study included equilibrium simulations to determine densities and melting temperatures, non-equilibrium simulations for stress-strain and Young moduli determination, mechanical cleaving to identify surface species resulting from material fragmentation, and shock compression simulations to elucidate chemical reactions activated by some external energy sources. The results indicate that material properties such as densities, phase transition temperatures, and Young moduli are accurately reproduced by the ReaxFF-CHO force field. The reactive dynamics analysis yielded crucial insights into the surface composition of fragmented polymers. Both polymers exhibited backbone breakage, leaving -CH2· and -CH·- radicals as terminals. PP demonstrated substantial fragmentation, while PS showed a tendency to develop crosslinks. A detailed analysis of chemical reactions resulting from increasing activation due to increasing value of compression pressure is presented and discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Interaction of β-D-glucopyranuronic acid (GlcA), N-acetyl-β-D-glucosamine (GlcNAc), N-acetyl-β-D-galactosamine (GalNAc) and two natural decameric glycosaminoglycans, hyaluronic acid (HA) and Chondroitin (Ch) with carboxylated carbon nanotubes, were studied using molecular dynamics simulations in a condensed phase. The force field used for carbohydrates was the GLYCAM-06j version, while functionalized carbon nanotubes (fCNT) were described using version two of the general amber force field. We found a series of significant differences in carbohydrate-fCNT adsorption strength depending on the monosaccharide molecule and protonation state of surface carboxyl groups. GlcNAc and GalNAc reveal a strong adsorption on fCNT with deprotonated carboxyl groups, and a slightly weaker adsorption on the fCNT with protonated carboxyl groups. On the contrary, GlcA weakly adsorbs on fCNT. The change in protonation state of surface carboxyl groups leads to the reversal orientation of GlcNAc and GalNAc in reference to the fCNT surface, while GlcA is not sensitive to that factor. Adsorption of decameric oligomers on the surface of fCNT weakens with the increasing number of monosaccharide units. Chondroitin adsorbs weaker than hyaluronic acid and incorporation of four Ch molecules leads to partial detachment of them from the fCNT surface. The glycan-fCNT interactions are strong enough to alter the conformation of carbohydrate backbone; the corresponding conformational changes act toward a more intensive contact of glycan with the fCNT surface. Structural and energetic features of the adsorption process suggest the CH-π interaction-driven mechanism.

Due to their unique structure, poly(amidoamine) (PAMAM) dendrimers can bind active ingredients in two ways: inside the structure or on their surface. The location of drug molecules significantly impacts the kinetics of active substance release and the mechanism of internalization into the cell. This study focuses on the effect of the protonation degree of the G4PAMAM dendrimer and the anticancer drug 5-fluorouracil (5FU) on the efficiency of complex formation. The most favorable conditions for constructing the G4PAMAM-5FU complex are a low degree of protonation of the dendrimer molecule with the drug simultaneously present in a deprotonated form. The fluorine components in the XPS spectra confirm the formation of the stable complex. Through SAXS and DLS methods, a decrease in the dendrimer's molecular size resulting from protonation changes at alkaline conditions was demonstrated. The gradual closure of the dendrimer structure observed at high pH values makes it difficult for the 5FU molecules to migrate to the interior of the support structure, thereby promoting drug immobilization on the surface. The 1 H NMR and DOSY spectra indicate that electrostatic interactions determine the complex formation process. Through MD simulations, the localization profile and the number of 5FU molecules forming the complex were visualized on an atomic scale.

In this paper, we present a number of novel pure-carbon structures generated from cyclo[18]carbon. Due to the very high reactivity of cyclo[18]carbon, it is possible to link these molecules together to form bigger molecular systems. In our studies, we generated new structures containing 18, 36 and 72 carbon atoms. They are of different shapes including ribbons, sheets and tubes. All these new structures were obtained in virtual reactions driven by external forces. For every reaction, the energy requirement was evaluated exactly when the corresponding transition state was found or it was estimated through our new approach. A small HOMO-LUMO gap in these nanostructures indicates easy excitations and the multiple bonds network indicates their high reactivity. Both of these factors suggest that some potential applications of the new nanostructures are as components of therapeutically active carbon quantum dots, terminal fragments of graphene or carbon nanotubes obtained after fracture or growing in situ in catalytic reactions leading to the formation of carbonaceous materials.

The work deals with molecular dynamics (MD) simulations of protonated, human telomeric i-motif deoxyribonucleic acid (DNA) with functionalized graphene. We studied three different graphene sheets: unmodified graphene with hydrogen atoms attached to their edges and two functionalized ones. The functionalization of graphene edge consists in attaching partially protonated or dissociated amine and carboxyl groups. We found that in all cases the protonated i-motif adsorbs strongly on the graphene surface. The biased MD simulations showed that the work necessary to drag the i-motif out from amine-doped graphene is about twice larger than that in other cases. In general, the system i-motif/amine-doped graphene stands out from the rest, e.g., in this case, the i-motif adsorbs its side with 3' and 5' ends oriented in the opposite to surface direction. In other cases, the DNA fragment is adsorbed to graphene by 3' and 5' ends. In all cases, the adsorption on graphene influences the i-motif internal structure by changing the distances between i-motif strands as well as stretching or shortening the DNA chain, but only in the case of amine-doped graphene the adsorption affects internal H-bonds formed between nucleotides inside the i-motif structure.

Cytosine-rich DNA sequences are able to fold into noncanonical structures, in which semi-protonated cytosine pairs develop extra hydrogen bonds, and these bonds are responsible for the overall stability of a structure called the i-motif. The i-motif can be formed in many regions of the genome, but the most representative is the telomeric region in which the CCCTAA sequences are repeated thousands of times. The ability to reverse folding/unfolding in response to pH change makes the above sequence and i-motif very promising components of nanomachines, extended DNA structures, and drug carriers. Molecular dynamics analysis of such structures is highly beneficial due to direct insights into the microscopic structure of the considered systems. We show that Amber force fields for DNA predict the stability of the i-motif over a long timescale; however, these force fields are not able to predict folding of the cytosine-rich sequences into the i-motif. The reason is the kinetic partitioning of the folding process, which makes the transitions between various intermediates too time-consuming in atomistic force field representation. Application of coarse-grained force fields usually highly accelerates complex structural transitions. We, however, found that three of the most popular coarse-grained force fields for DNA (oxDNA, 3SPN, and Martini) were not able to predict the stability of the i-motif structure. Obviously, they were not able to accelerate the folding of unfolded states into an i-motif. This observation must be strongly highlighted, and the need to develop suitable extensions of coarse-grained force fields for DNA is pointed out. However, it will take a great deal of effort to successfully solve these problems.

This works deals with analysis of properties of a carbon nanotube, the tips of which were functionalized by short cytosine-rich fragments of ssDNA. That object is aimed to work as a platform for storage and controlled release of doxorubicin in response to pH changes. We found that at neutral pH, doxorubicin molecules can be intercalated between the ssDNA fragments, and formation of such knots can effectively block other doxorubicin molecules, encapsulated in the nanotube interior, against release to the bulk. Because at the neutral pH, the ssDNA fragments are in form of random coils, the intercalation of doxorubicin is strong. At acidic pH, the ssDNA fragments undergo folding into i-motifs, and this leads to significant reduction of the interaction strength between doxorubicin and other components of the system. Thus, the drug molecules can be released to the bulk at acidic pH. The above conclusions concerning the storage/release mechanism of doxorubicin were drawn from the observation of molecular dynamics trajectories of the systems as well as from analysis of various components of pair interaction energies.

In this work, we studied, using computational methods, the protonation reactions of telomeric DNA fragments being due to interaction with carboxylated carbon nanotubes. The applied computational methodology is divided into two stages. (i) Using classical molecular dynamics, we generated states in which carboxyl groups are brought to the vicinity of nitrogen atoms within the cytosine rings belonging to the DNA duplex. (ii) From these states, we selected two systems for systematic quantum chemical studies aimed at the analysis of proton-transfer reactions between the carboxyl groups and nitrogen atoms within the cytosine rings. Results of molecular dynamics calculations led to the conclusion that sidewall-functionalized carbon nanotubes deliver carboxyl groups slightly more effectively than the on-tip-functionalized ones. The latter can provide carboxyl groups in various arrangements and more diverse quality of approach of carboxyl groups to the cytosines; however, the differences between various arrangements of carboxyl groups are still not big. It was generally observed that narrow nanotubes can access the cytosine pocket easier than wider ones. Quantum chemical calculations led however to the conclusion that a direct proton transfer from the carboxyl group to the nitrogen atom within the cytosine ring is impossible under normal conditions. Precisely, we detected either very high activation barrier for the proton-transfer reaction or instability of the reaction product, i.e., its spontaneous decomposition toward reaction substrates.

The controlled delivery and release of drug molecules at specific targets increases the therapeutic efficacy of treatment. This paper presents a triple complex which is a new potential drug delivery system. Triple complex contains single-walled carbon nanotubes, Congo red, and doxorubicin. Nanotubes are built of a folded graphene layer providing a large surface for binding Congo red via "face-to-face" stacking which markedly increases the binding capacity of the carrier. Congo red is a compound that self-associates to form supramolecular ribbon-like structures, which are able to bind some drugs by intercalation. The nanotube-Congo red complex can bind the model drug doxorubicin. Thus, a new triple carrier system was obtained. The aim of this paper is to present studies on the controlled release of a model anticancer drug from a triple carrier system through pH changes. The specific aim of the study was to model the structure of the obtained experimental systems and to compare the changes in the average energy of interaction between its components induced by pH changes. The studies also aimed to compare the intensity of pH-dependent changes in hydrodynamic diameters of individual components of the triple carrier system. The effect of pH changes on the stability of the analyzed systems was examined using the molecular modeling method and dynamic light scattering. The decrease in pH influenced the structure and stability of the analyzed triple systems and ensured efficient drug release. The changes in hydrodynamic diameters of the obtained fractions were examined with the use of dynamic light scattering and were confirmed by computer simulation methods. The formulation presented in this paper shows potential for a therapeutic application owing to its high drug binding capacity and pH-dependent release. This ensures prolonged local action of the drug. The results reveal that the studied complex fulfills the basic requirements for its potential use as drug carrier, thus reducing side effects and enhancing pharmacological efficacy of drugs.

This work deals with molecular dynamics simulations of systems composed of telomeric dsDNA fragments, iG, and functionalized carbon nanotubes, fCNT. The iG contains 90 nucleotides in total and in its middle part the noncanonical i-motif and G-quadruplex are formed. Two chiralities of the fCNT were used, i.e., (10,0) and (20,0) and these nanotubes were either on-tip functionalized by guanine containing functional groups or left without functionalization. We proposed a dedicated computational procedure, based on the replica exchange concept, for finding a thermodynamically optimal conformation of iG and fCNT without destroying the very fragile noncanonical parts of the iG. We found that iG forms a V-shape spatial structure with the noncanonical fragments located at the edge and the remaining dsDNA strands forming the arms of V letter. The optimal configuration of iG in reference to fCNT strongly depends on the on-tip functionalization of the fCNT. The carbon nanotube without functionalization moves freely between the dsDNA arms, while the presence of guanine residues leads to immobilization of the fCNT and preferential location of the nanotube tip near the junction between the dsDNA duplex and i-motif and G-quadruplex. We also studied how the presence of fCNT affects the stability of the i-motif at the neutral pH when the cytosine pairs are nonprotonated. We concluded that carbon nanotubes do not improve the stability of the spatial structure of i-motif also when it is a part of a bigger structure like the iG. Such an effect was described in literature in reference to carboxylated nanotubes. Our current results suggest that the stabilization of i-motif is most probably related to easy formation of semiprotonated cytosine pairs at neutral pH due to interaction with carboxylated carbon nanotubes.

This work deals with molecular dynamics simulations of human telomeric i-motif DNA interacting with functionalized single-walled carbon nanotubes. We study two kinds of i-motifs differing by the protonation state of cytosines, i.e., unprotonated ones representative to neutral pH and with half of the cytosines protonated and representative to acidic conditions. These i-motifs interact with two kinds of carbon nanotubes differing mainly in chirality (diameter), i.e., (10, 0) and (20, 0). Additionally, these nanotubes were on-tip functionalized by amino groups or by guanine- containing residues. We found that protonated i-motif adsorbs strongly, although not specifically, on the nanotube surfaces with its 3' and 5' ends directed toward the surface and that adsorption does not affect the i-motif shape and hydrogen bonds existing between C:C + pairs. The functional groups on the nanotube tips have minimal effect either on position of i-motif or on its binding strength. Unprotonated i-motif, in turn, deteriorates significantly during interaction with the nanotubes and its binding strength is rather high as well. We found that (10, 0) nanotubes destroy the i-motif shape faster than (20, 0). Moreover the i-motif either tries to wrap the nanotube or migrates to its tip and becomes immobilized due to interaction with guanine residue localized on the nanotube tip and attempts to incorporate its 3' end into the nanotube interior. No hydrogen bonds exist within the unprotonated i-motif prior to and after adsorption on the nanotube. Thus, carbon nanotubes do not improve the stability of unprotonated i-motif due to simple adsorption or just physical interactions. We hypothesize that the stabilizing effect of carbon nanotubes reported in the literature is due to proton transfer from the functional group in the nanotube to cytosines and subsequent formation of C:C + pairs.

Molecular dynamics simulations were employed to study the properties of G-quadruplex and i-motif secondary DNA structures formed within the canonical telomere fragment of the Watson-Crick duplex. These secondary structures were built symmetrically in the same place of the duplex and were subjected to the analysis in standard unbiased simulations and using metadynamics scheme for the determination of potential of mean force associated with the enforced unfolding of the i-motif parts of the systems. Also, enforced formation of i-motif structures, starting from partially unfolded duplex, were studied in order to find whether formation of i-motif facilitates spontaneous formation of G-quadruplex. We found that i-motif formed from single stranded DNA is unstable at neutral pH and room temperature. On the other hand, the i-motif is strongly stabilized by the presence of complementary G-quadruplex, which should be the most likely configuration when these secondary structures form from double stranded DNA. The stabilization is observed either in neutral or in acidic pH though in the neutral case the i-motif can also reveal considerable stability in the hairpin configuration. We did not observe spontaneous folding of the guanine-rich strand into the G-quadruplex when the cytosine rich strand was dragged to i-motif configuration. This observation suggests that both folding and unfolding transitions are kinetically blocked.

In this work we have analyzed the influence of various factors on the transverse relaxation times T2 of water protons in suspension of magnetic nanoparticles. For that purpose we developed a full molecular dynamics force field which includes the effects of dispersion interactions between magnetic nanoparticles and water molecules, electrostatic interactions between charged nanoparticles and magnetic dipole-dipole and dipole-external field interactions. We also accounted for the magnetization reversal within the nanoparticles body frames due to finite magnetic anisotropy barriers. The force field together with the Langevin dynamics imposed on water molecules and the nanoparticles allowed us to monitor the dephasing of water protons in real time. Thus, we were able to determine the T2 relaxation times including the effects of the adsorption of water on the nanoparticles' surfaces, thermal fluctuations of the orientation of nanoparticles' magnetizations as well as the effects of the core-shell architecture of nanoparticles and their agglomeration into clusters. We found that there exists an optimal cluster size for which T2 is minimized and that the retardation of water molecules motion, due to adsorption on the nanoparticles surfaces, has some effect in the measured T2 times. The typical strengths of the external magnetic fields in MRI are enough to keep the magnetizations fixed along the field direction, however, in the case of low magnetic fields, we observed significant enhancement of T2 due to thermal fluctuations of the orientations of magnetizations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In this paper we propose an implicit solvent model which can be used in molecular dynamics simulations of systems comprising colloid nanoparticles and carbon nanotubes. Such systems, due to finite nanometer sizes of both components cannot be accurately approximated by a smaller slab geometry and thus represent a particularly difficult case in terms of computer simulations. In particular, nanoparticle sizes of a few tens of nanometers lead to billions of solvent molecules in a simulation box and require very long cut-off distances which drastically increases computation time. To overcome this difficulty we develop an implicit solvent model based on Hamaker theory of dispersive interactions. The predictions of our model are verified by comparison with the exact model, involving all atoms and full description of pair interactions. The proposed model correctly predicts the work of adhesion and average configuration in colloid - carbon nanotube systems. Moreover, application of the Langevin dynamics reproduces the dynamic behaviour of the exact model either., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Two generalizations of the statistical rate theory (SRT) approach have been developed for the kinetics of adsorption/desorption on/from heterogeneous surfaces and then compared to each other. The first of them is an improved version of the description based on the condensation approximation (CA) used by us. The other one is an exact generalization for the Langmuir model of adsorption. The latter generalization does not lead to simple analytical expressions for the rate of adsorption/desorption as the CA approach does for typical adsorption energy distributions. The comparison of these two approaches suggests, however, that at small and very high surface coverages the CA approach may not be sufficiently accurate. Very intriguing results are obtained when the developed SRT kinetic equations are applied to describe the kinetics of sorption in carbon molecular sieves. It appears that the fit of experimental data is then equally good as that obtained by assuming that the rate of sorption is controlled by surface diffusion in pores. Also, it is shown that the square-root dependence on time of adsorption at small initial coverages cannot be treated as a definite proof for that sorption proceeds via surface diffusion, as is commonly assumed.

We propose a model of the dissociative adsorption of hydrogen on nickel single-crystal face. In this model, we treat the Ni(100) surface as a strongly correlated energetically heterogeneous surface, because the density functional theory (DFT) studies indicate that hydrogen atoms may adsorb either on hollow sites (energetically more favorable, binding energy 48 kJ/mol H) or bridge sites with the binding energy less by 11 kJ/mol H. The essential assumption of the proposed model is that the dissociation of the hydrogen molecule is possible only over the topmost Ni atom, and the resulting H atoms may adsorb either on two free hollow sites (but the adjacent bridge sites must be free) or two bridge sites (the adjacent hollow sites must be free). If the above condition is not fulfilled, then the dissociation and adsorption are impossible. The second assumption is that the rate (probability) of the associative desorption is limited by the rate of diffusion of H atoms on the surface. This is because the two H atoms desorb, giving an H2 molecule, only when they meet on two adjacent hollow-bridge sites. Our model recovers very well the behavior of the experimental equilibrium adsorption isotherms as well as kinetic isotherms. As a result, we stated that hydrogen atoms are not completely free on the surface, but they cannot also be considered localized at room and elevated temperatures. Additionally, while analyzing the kinetic adsorption isotherms, we stated that the rate-limiting step during the dissociative adsorption of H2 is the disintegration of the activated complex and the subsequent adsorption of hydrogen atoms.