Insights into Transfer of Supramolecular Doxorubicin/Congo Red Aggregates through Phospholipid Membranes.

Doxorubicin (DOX) is a commonly used chemotherapeutic drug, from the anthracycline class, which is genotoxic to neoplastic cells via a DNA intercalation mechanism. It is effective and universal; however, it also causes numerous side effects. The most serious of them are cardiotoxicity and a decrease in the number of myeloid cells. For this reason, targeted DOX delivery systems are desirable, since they would allow lowering the drug dose and therefore limiting systemic side effects. Recently, synthetic dyes, in particular Congo red (CR), have been proposed as possible DOX carriers. CR is a planar molecule, built of a central biphenyl moiety and two substituted naphthalene rings, connected with diazo bonds. In water, it forms elongated ribbon-shaped supramolecular structures, which are able to selectively interact with immune complexes. In our previous studies, we have shown that CR aggregates can intercalate DOX molecules. In this way, they preclude DOX precipitation in water solutions and increase its uptake by MCF7 breast cancer cells. In the present work, we further explore the interactions between DOX, CR, and their aggregates (CR/DOX) with phospholipid membranes. In addition to neutral molecules, the protonated doxorubicin form, DXP, is also studied. Molecular dynamics simulations are employed to study the transfer of CR, DOX, DXP, and their aggregates through POPC bilayers. Interactions of CR, DOX, and CR/DOX with model monolayers are studied with Langmuir trough measurements. This study shows that CR may support the transfer of doxorubicin molecules into the bilayer. Both electrostatic and van der Waals interactions with lipids are important in this respect. The former promote the initial stages of the insertion process, the latter keep guest molecules inside the bilayer.

Insights into short chain polyethylene penetration of phospholipid bilayers via atomistic molecular dynamics simulations.

The escalation of global plastic production, reaching an annual output of 400 million tons, has significantly intensified concerns regarding plastic waste management. This has been exacerbated by improper recycling and disposal practices, contributing to the impending crisis of plastic pollution. Predictions indicate that by 2025, the environment will bear the burden of over ten billion metric tons of accumulated plastic waste. This situation has led to the concerning release of microplastics and nanoplastics (NPs) into the environment as plastic materials degrade, thereby posing risks to both ecosystems and human health. Nanoparticle interactions with living organisms have garnered significant attention due to their potential to disrupt vital biological processes. Of particular interest are lipid membranes, acting as crucial gatekeepers, underscoring the importance of comprehending the intricate process of NP penetration. Molecular dynamics (MD) simulations serve as a robust tool, offering molecular-level insights into these intricate interactions. In this study, we leverage all-atom MD simulations to delve into the interactions between lipid bilayers and polyethylene (PETH) chains of varying lengths. The investigation spans diverse lipid bilayer compositions-ranging from pure POPC to POPC:DPPC mixtures-revealing how PETH accommodates itself, adopts extended conformations, and influences membrane structure and ordering. Significantly, while longer PETH chains demonstrate limited passive diffusion, their potential to penetrate bilayers over extended timescales emerges as a significant revelation. Overall, this research significantly advances our comprehension of NP-membrane interactions, shedding light on the potential environmental and health implications that lie ahead.

Nucleoside Analog Reverse-Transcriptase Inhibitors in Membrane Environment: Molecular Dynamics Simulations.

The behavior of four drugs from the family of nucleoside analog reverse-transcriptase inhibitors (zalcitabine, stavudine, didanosine, and apricitabine) in a membrane environment was traced using molecular dynamics simulations. The simulation models included bilayers and monolayers composed of POPC and POPG phospholipids. It was demonstrated that the drugs have a higher affinity towards POPG membranes than POPC membranes due to attractive long-range electrostatic interactions. The results obtained for monolayers were consistent with those obtained for bilayers. The drugs accumulated in the phospholipid polar headgroup region. Two adsorption modes were distinguished. They differed in the degree of penetration of the hydrophilic headgroup region. Hydrogen bonds between drug molecules and phospholipid heads were responsible for adsorption. It was shown that apricitabine penetrated the hydrophilic part of the POPC and POPG membranes more effectively than the other drugs. Van der Waals interactions between S atoms and lipids were responsible for this.

Congo Red as a Supramolecular Carrier System for Doxorubicin: An Approach to Understanding the Mechanism of Action.

The uptake and distribution of doxorubicin in the MCF7 line of breast-cancer cells were monitored by Raman measurements. It was demonstrated that bioavailability of doxorubicin can be significantly enhanced by applying Congo red. To understand the mechanism of doxorubicin delivery by Congo red supramolecular carriers, additional monolayer measurements and molecular dynamics simulations on model membranes were undertaken. Acting as molecular scissors, Congo red particles cut doxorubicin aggregates and incorporated them into small-sized Congo red clusters. The mixed doxorubicin/Congo red clusters were adsorbed to the hydrophilic part of the model membrane. Such behavior promoted transfer through the membrane.

The lung surfactant activity probed with molecular dynamics simulations.

The surface of pulmonary alveolar subphase is covered with a mixture of lipids and proteins. This lung surfactant plays a crucial role in lung functioning. It shows a complex phase behavior which can be altered by the interaction with third molecules such as drugs or pollutants. For studying multicomponent biological systems, it is of interest to couple experimental approach with computational modelling yielding atomic-scale information. Simple two, three, or four-component model systems showed to be useful for getting more insight in the interaction between lipids, lipids and proteins or lipids and proteins with drugs and impurities. These systems were studied theoretically using molecular dynamic simulations and experimentally by means of the Langmuir technique. A better understanding of the structure and behavior of lung surfactants obtained from this research is relevant for developing new synthetic surfactants for efficient therapies, and may contribute to public health protection.

Charge distributions for molecular dynamics simulations from self-consistent polarization method.

Partial atomic charges are important force field parameters. They are usually computed by applying quantum-chemical calculations and the assumed population scheme. In this study polarization consistent scheme of deriving a charge distribution inside solute molecule is proposed. The environment effect is explicitly taken into account by distributing solvent molecules around the solute target. The performed analysis includes a few computational schemes (HF, MP2, B3LYP, and M026X), basis sets (cc-pvnz, n = 2, 3, …, 6), and electrostatically derived charge distributions (KS, CHELP, CHELPG, and HLY). It is demonstrated that the environment effect is very important and cannot be disregarded. The second solvation shell should be included to achieve the charge convergence. Huge corrections to charge distribution are due to induction and dispersion. The B3LYP/cc-pvqz level of theory is recommended for deriving the charges within self-consistent polarization scheme.

Impact of Doxorubicin on Self-Organization of Congo Red: Quantum Chemical Calculations and Molecular Dynamics Simulations.

Quantum-chemical calculations and molecular dynamics simulation were applied to a model self-organization process of Congo red (CR) molecules in aqueous solution and the impact of doxorubicin (DOX) molecules on such a process. It was demonstrated that both pure CR/CR and mixed CR/DOX dimers were stable. Van der Waals interactions between aromatic units were responsible for a stacked dimer formation. An important source of stabilization in the CR/CR dimer was the polarization energy. In the CR/DOX mixed dimer long range, electrostatic interactions were the main driving force leading to complexation. An implicit solvent model showed that the formation of the CR/CR dimer was favored over the CR/DOX one. Molecular dynamics simulations demonstrated rapid complexation. In the pure CR system, short sequences of ribbon-like structures were formed. Such structures might be glued by hydrogen bonds to form bigger complexes. It was shown that the aromatic part of the DOX molecule enters CR ribbons with the sugar part covering the CR ribbons. These findings demonstrated that CR may find applications as a carrier in delivering DOX molecules; however, further more extensive investigations are required.

Elongation method with intermediate mechanical and electrostatic embedding for geometry optimizations of polymers.

The elongation method with intermediate mechanical and electrostatic embedding (ELG-IMEE) is proposed. The electrostatic embedding uses atomic charges generated by a charge sensitivity analysis (CSA) method and parameterized for three different population analyses, namely, the Merz-Singh-Kollman scheme, the charge model 5, and the atomic polar tensor. The obtained CSA models were tested on two model systems. Test calculations show that the electrostatic embedding provides several times of decrease in the difference of energies of testing and reference calculations in comparison with the conventional elongation approach (ELG). The mechanical embedding is implemented in a combination of the conventional elongation method and the ONIOM approach. Moreover, it was demonstrated that the geometry optimization with the ELG-IMEE reduces the errors in the optimized structures by about one order in root-mean-square deviation, when compared to ELG.

Lung surfactant monolayer - A good natural barrier against dibenzo-p-dioxins.

The present study deals with interaction of two air pollutants: dibenzodioxin, DD, and its' monochlorinated derivative, 2-chlorodibenzodioxin, 2CLDD, with models of the lung surfactant (LS) system. A monolayer composed of DPPC and POPC in 1:1 molar ratio was used as a model of LS. One component monolayers of DPPC and POPC were also examined, to model the interiors of LC and LE domains in LS, respectively. Molecular dynamics simulations and measurements of surface pressure isotherms, as well as polarization modulation-infrared reflection-absorption spectra were employed to study the influence of dioxins on the monolayers. We demonstrate, that both dioxins adsorb and accumulate in the hydrophobic parts of all three monolayers. DD molecules prefer flat orientation on the surface at large areas. Upon compression, they lift and orient perpendicularly to the monolayer. Flat orientation of DD molecules leads to their large surface area. In consequence they preferentially locate in vicinity of unsaturated chains of POPC - they are small enough to fill void spaces created by kinks in unsaturated chains. 2CLDD orient along monolayer normal already at the largest areas and preference for POPC was not observed for them. In laterally relaxed states, a condensing effect, connected with reduction of surface area available to the lipids was observed for both dioxins. In the case of 2CLDD, additional locally ordering influence of dioxin molecules was detected. In compressed states, the presence of dioxin molecules hinders alignment and uniform ordering of lipid chains.

The role of DPPG in lung surfactant exposed to benzo[a]pyrene.

Lung surfactant (LS) occurs at the air-water interface in the alveoli. Its main function is to reduce the work needed to expand the alveoli during inhalation and prevent the alveolar collapse during exhalation. Disturbance of this complex interfacial system by the uptake of pollutant molecules can lead to changes in fluidity, permeability, phase separation and domain formation, which in turn can lead to serious impairment in lung function. Knowledge of the LS-pollutant interaction is essential for understanding the mechanism of this process. In this study, we investigate the interaction of LS models with benzo[a]pyrene (BaP). Dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylglycerol (DPPG) sodium salt, and their 4 : 1 mixture are used as LS models. Surface pressure-area isotherms and molecular dynamics simulations are employed to study the properties of LS monolayers. It was found that the addition of BaP has a destabilizing effect on the mixed DPPC/DPPG monolayer, manifested by the decrease in surface pressure. Compression of a monolayer during a respiratory cycle may expel BaP to the bulk solution. It was demonstrated that DPPG is an active component that prevents the BaP molecule from entering the water subphase; as a minor component of LS it can effectively reduce this process. In addition, the presence of BaP in LS models induces the reduction of monolayer hydration in the hydrophilic region and the increase in chain ordering in the hydrophobic region. The observed changes in monolayer fluidity and phase behavior can be a source of various lung function disorders.

Modeling Lung Surfactant Interactions with Benzo[a]pyrene.

By reducing the surface tension of the air-water interface in alveoli, lung surfactant (LS) is crucial for proper functioning of the lungs. It also forms the first barrier against inhaled pathogens. In this study we inspect the interactions of LS models with a dangerous air pollutant, benzo[a]pyrene (BaP). Dipalmitoylphosphatidylcholine (DPPC), 1-palmitoyl-2-oleoylphosphatidylcholine, and their 1:1 mixture are used as LS models. Pressure-area isotherms are employed to study macroscopic properties of the monolayers. We find that addition of BaP has a condensing effect, manifested by lowering the values of surface pressure and shifting the isotherms to smaller areas. Atomistic details of this process are examined by means of molecular dynamics simulations. We show that initially BaP molecules are accumulated in the monolayers. Upon compression, they are forced to the headgroups region and eventually expelled to the subphase. BaP presence results in reduction of monolayer hydration in the hydrophilic region. In the hydrophobic region it induces increased chain ordering, reduction of monolayer fluidity, and advances transition to the liquid condensed phase in the DPPC system.

Formation of ß-cyclodextrin complexes in an anhydrous environment.

The formation of inclusion complexes of ß-cyclodextrin was studied at the melting temperature of guest compounds by differential scanning calorimetry. The complexes of long-chain n-alkanes, polyaromatics, and organic acids were investigated by calorimetry and IR spectroscopy. The complexation ratio of ß-cyclodextrin was compared with results obtained in an aqueous environment. The stability and structure of inclusion complexes with various stoichiometries were estimated by quantum chemistry and molecular dynamics calculations. Comparison of experimental and theoretical results confirmed the possible formation of multiple inclusion complexes with guest molecules capable of forming hydrogen bonds. This finding gives new insight into the mechanism of formation of host-guest complexes and shows that hydrophobic interactions play a secondary role in this case. Graphical abstract The formation of complexes of ß-cyclodextrin with selected n-alkanes, polyaromatics, and organic acids in an anhydrous environment is studied by differential scanning calorimetry, IR spectroscopy, and molecular modeling. The results obtained confirm the possible formation of multiple inclusion complexes with guest molecules capable of forming hydrogen bonds and give a new perspective on the mechanism of formation of host-guest complexes.