The study explores the molecular-level binding of a set of vector ligands─folate, methotrexate, raltitrexed, pemetrexed, 5-methyltetrahydrofolate, and pteroyl ornithine─to the membrane-embedded folate receptor-α, a relevant target in cancer therapy. Statistical analysis of data from molecular dynamics simulations is performed to quantify the suitability of the ligands as constituents of active targeting drug delivery systems. The preferred binding modes of each ligand are identified and discussed in terms of ligand positioning and mechanism of binding. Interaction maps and structures of representative clusters highlight the key amino acid residues involved in the ligand-receptor complexes and provide clues for the attachment mechanism of the ligands. The results reveal that the complex formation is primarily driven by dispersion forces, particularly involving the pterin and aminobenzoate fragments, with additional stabilization from hydrogen bonds and electrostatics. Specific interaction patterns are identified for each ligand, which provide rationalization of the experimentally registered dissimilar behavior of the studied vectors toward the receptor. On the basis of the performed analyses, general guidelines for ligands to bind to the active site of the protein are formulated. Among the addressed ligands, only folate and raltitrexed comply with the requirements and bind sustainably to the receptor active site, outlining them as effective vectors for folate-based drug-delivery systems.

Iron oxides, including hematite (α-Fe2O3), magnetite (Fe3O4), and maghemite (γ-Fe2O3), play central roles in catalysis, corrosion, environmental remediation, magnetic nanotechnology, and energy storage. Molecular dynamics simulations have become an essential tool for understanding their structural, magnetic, and interfacial behavior at the atomic scale. This review provides a comprehensive overview of MD methodologies applied to these materials, spanning classical force fields, reactive force fields, ab initio molecular dynamics, and emerging machine learning interatomic potentials. Particular emphasis is placed on facet-dependent surface chemistry, especially the contrast between compact (111) and open (110) planes, and on adsorption processes involving water, nitrogen-containing molecules, and representative organic compounds. The review highlights recent advances in force field development, redox modeling, and multiscale simulation strategies while critically identifying limitations related to charge transfer, mixed valence, vacancy ordering, and magnetic-chemical coupling. Finally, future perspectives are outlined toward quantitatively predictive, facet-resolved, and magnetically aware simulations of iron oxide interfaces. These developments are expected to tightly link atomistic insights with experimental observations and guide the rational design of iron oxide-based functional materials.

The erosion–corrosion mechanism of low-alloy steel in high-ammonia steam generator’s chemistry is studied by in situ impedance spectroscopy coupled with an in-depth analysis of formed oxides using glow discharge optical emission spectroscopy. A novel electrode setup that ensures turbulent conditions in the vicinity of the steel sample is used. The effect of temperature (130–230 °C) and flow rate (2–10 dm3 h−1) is investigated. The energy of adsorption of ammonia depends on temperature and is estimated using molecular dynamic simulations. The kinetic and transport parameters of the corrosion process are estimated via the regression of the experimental impedance spectra to the transfer function of the Mixed-Conduction Model for oxide films. Conclusions are drawn about the effect of Cr in the alloy, and the temperature and flow rate on the corrosion mechanism.

Magnetite (Fe3O4) provides a protective corrosion layer in the steam generators of nuclear power plants. The presence of monoethanolamine (MEA) in coolant water has a beneficial effect on corrosion processes. In that context, the adsorption of MEA and ethanol–ammonium cation on the {111} surface of magnetite was studied using the molecular dynamics (MD) method. A modified version of the mechanical force field (ClayFF) was used. The systems were simulated at different temperatures (423 K; 453 K; 503 K). Surface coverage data were obtained from adsorption simulations; the root-mean-square deviation (RMSD) of the target molecules were calculated, and their minimum distance to the magnetite surface was traced. The potential and adsorption energies of MEA were calculated as a function of temperature. It has been established that the interaction between MEA and magnetite is due to electrostatic phenomena and the adsorption rate increases with temperature. A comparison was made with existing experimental results and similar MD simulations.

The major components of cell membranes are phospholipids. Due to their amphiphilic structure, in a solution they arrange in bilayers. The phase behavior of lipid bilayers and thus their functions, such as cellular organization, cellular transport, membrane fusion, drug delivery, and others, are susceptible to temperature changes and/or admixing with biologically active materials. A typical representative of phospholipids is SOPC (1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine) possessing a saturated hydrocarbon acyl chain and an unsaturated one, exhibiting a single cis double bond. Cholesterol plays a primordial role in maintaining the mechanical stability of the cell membrane. We present a comprehensive review of the phase behavior of the binary mixture of SOPC with cholesterol as a function of the temperature explored via atomistic molecular dynamics and Slipids force field in the vicinity of the experimental melting point, T m = 279 K, corresponding to the temperature driven phase transition from the gel phase (Lβ) to the liquid disordered phase (Lα). The behavior of the thermodynamic properties and structural characteristics with different concentrations of cholesterol show that the pure SOPC bilayer and its counterpart mixed with 10 mol % cholesterol exhibit phase transitions at 277 and 276 K, respectively, and that cholesterol reinforces the fluidity of the bilayer leading to the emergence of a liquid ordered phase (Lo). At cholesterol contents larger than 30 mol %, the bilayer exhibits a liquid ordered phase (Lo) at any temperature. The ensuing phase diagram is found to reproduce reasonably well its counterpart constructed experimentally.

The present study proposes an atomistic molecular dynamics model system of a magnetite (Fe3O4) {111} surface. The effect of temperature on the adsorption process of ammonia (NH3) at low concentrations in the aqueous phase has been considered. The molecular dynamics simulations were carried out using the Clay force field (Clay FF) with a modification for the iron atoms in the NPT ensemble at a pressure of 90 bar. The considered system was heated in a temperature range from 293 to 473 K, and additional relaxations were performed at temperatures of interest. Within the scope of this study, the basic parameters of the magnetite surface were calculated and the distances between the ammonia molecules and the surface were determined. A general idea of the degree and rate of adsorption at specific temperatures was obtained. The calculation results were compared to the experimental data where possible and to other available simulations of adsorption processes on metal oxides.

We explore the phase behavior of lipid bilayers containing SOPC (1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine) with various molar concentrations (0 mol%, 10 mol% and 30 mol%) of cholesterol. To this end, we performed extensive atomistic molecular dynamics simulations in conjunction with the Slipids force field with optimized parameters for the headgroups of phospholipids. We computed thermodynamic and structural quantities describing the ordering of the tails, the mobility of the heads and the arrangement of the lipids in the bilayers. We analyzed the behavior of the named quantities over the temperature range between 271 K and 283 K, where the experimentally determined melting temperature, Tm=279 K, lies, as well as at 400 K, which is used as a reference temperature. The obtained results are compared to available experimental data along with the outcome from molecular dynamics simulations of similar phospholipids containing different amounts of cholesterol. In the temperature interval of interest, we found evidence of the occurrence of a thermal-driven phase transition (melting) in both the pure system and the one with the lower concentration of cholesterol, while in the remaining system, the higher amount of cholesterol in the bilayer smears out the transitional behavior. Thus, we demonstrate the ability of the Slipids force field to predict the phase behavior of bilayers of SOPC and SOPC mixed with cholesterol.

Slipid (Stockholm lipids) force field is suitable for the description of the physical properties of biological membranes composed of phospholipids at room temperature. So far, its accuracy to reproduce the behavior of the thermodynamic and structural quantities of membranes at low temperatures has not yet been tested in sufficient details. In the present study, we compute some characteristic quantities of SOPC (1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine) using GROMACS in conjunction with Slipid force field. The initial configuration of the SOPC system composed of 128 lipid molecules distributed equally in each monolayer and 5120 water molecules was generated with the aid of CHARMM-GUI. Atomistic molecular dynamic (MD) simulations were performed at several temperatures. By virtue of a statistical analysis of trajectories, we computed the main structural parameters of the lipid molecules and thermodynamic quantities characterizing the phase behavior of the bilayer. The results are compared to available experimental data, as well as theoretical predictions. The Slipid force field was found to describe fairly well the structural behavior of the lipids at low temperatures.

We study the behavior of lipid bilayers composed of SOPC (1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine) with different concentrations of cholesterol, ranging from 10 mol% to 50 mol% at 273 K. To this end, we carry out extensive atomistic molecular dynamic simulations with the aid of the Slipid force field aiming at computing basic bilayer parameters, as well as thermodynamic properties and structural characteristics. The obtained results are compared to available relevant experimental data and the outcome of atomistic simulations performed on bilayers composed of analogous phospholipids. Our results show a good quantitative, as well as qualitative, agreement with the main trends associated with the concentration increase in cholesterol. Moreover, it comes out that a change in the behavior of the bilayer is brought about at a concentration of about 30 mol% cholesterol. At this very concentration, some of the bilayer properties are found to exhibit a saturation and a significant long-range ordering of the lipid molecules in the membrane shows up.

Abstract Many research efforts are devoted to improving the efficiency of chemotherapy. One of the aspects is to facilitate the transport of drugs across the cell membranes by attaching the therapeutics to a carrier molecule. The current study focuses on computational investigation of such a system with doxorubicin as the model drug, which is covalently bound to a cell-penetrating peptide. The correct description of its membrane translocation at the molecular level requires proper choice of the model membrane and of the simulation parameters. For the purpose, two phospholipid bilayers are built, one containing solely DPPC and another with mixed lipid content mimicking the composition of a human erythrocyte membrane. Atomistic molecular dynamics simulations are carried out in two types of periodic boundary conditions (2D and 3D PBC), in order to assess the effect of the periodicity dimensionality on the intermolecular interactions. The evolution of some basic characteristics of the bilayers and of the drug–peptide complex is tracked: mass density profiles, electrostatic potentials, lateral diffusion coefficients and areas per lipid, lipid-complex radial distribution functions, secondary structure of the peptide and orientation of the drug relative to the membrane. Thus, the influence of the periodic boundary conditions is quantified and it shows that the mixed system in 3D PBC is the most suitable for analysis of the translocation of the transporting moiety across cell membranes. Graphical Abstract The type of periodic boundary conditions, three-dimensional vs. two-dimensional (3D vs. 2D PBC), causes marked influence on the process of membrane penetration of doxorubicin carried by a cell-penetrating peptide, as evidenced by 1-µs-long atomistic MD simulations. Communicated by Ramaswamy H. Sarma

New types of imine switches containing an alkylated para-bis(2-thienyl)phenylene moiety have been synthesized and studied. A bis substituted 2,4-diiminotoluene with phenylene-thienyl unit has also been synthesized and studied to evaluate the bifunctional switching of the imine bonds. Fast E/Z response in toluene and acetonitrile under 365 nm UV-light illumination was observed. It was found that the thermally unstable Z isomers are recovered to E ones in the dark by different rate constants depending on the solvent polarity, which refers to the T-type photochromic switches. The DFT calculations have shown that the switched Z forms are characterized by near perpendicular (T-shaped) orientation of the aromatic amine rings with respect to the thiophene one. The emission exhibited a significant bathochromism varying the solvent polarity, with Stokes shifts reaching values in the order 10 000 cm-1, while the absorption remained almost unaffected. Therefore, the relationship between E/Z switching response and solvent sensitivity of the emissions was estimated. The behaviour of the compounds suggests a rapid T-type E/Z/E isomerization cycle and dynamic control over the light-driven geometrical changes of the imine bond.

Two novel, 7-hydroxyquinoline based, Schiff bases have been synthesized and their spectral properties have been investigated by combined use of optical and NMR spectroscopy and theoretical DFT calculations. The results indicate that 8-((phenylimino)methyl)quinolin-7-ol exists as a mixture of enol and two keto tautomers in solution, while 8-(((pentarfluorophenyl)imino)methyl)quinolin-7-ol is presented as a single enol form. Upon irradiation, in both compounds, through excited state intramolecular proton transfer mechanism, a rotation around the Cquin-CH bond occurs, indicating that they are suitable to be used as bistable switches. The back relaxation is faster comparing to the theoretical expectations, due to the additional flexibility around the azomethine bond. As a result of forming complexes with the acidic counter ion, no intramolecular rotation happens upon protonation with trifluoroacetic acid.

Cell membranes are constructed of phospholipids bilayers that may incorporate various biologically relevant admixtures, such as proteins, cholesterol, hydrocarbons to name a few. SOPC (1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine), is often used in fundamental studies to gain insights into the physico-chemical properties of lipid systems and liposomal carriers of bioactive systems. Cholesterol plays an important role in modulating the fluidity of lipid membranes, thus affecting its physical properties. We employed atomistic Molecular Dynamics in conjuction with the Slipids (Stockholm lipids) force field to study the effect of cholesterol on the physical characteristics of SOPC over an interval of temperatures in the vicinity of the experimental transition temperature from gel to liquid. We computed a number of thermodynamic and structural quantities to characterize samples of pure SOPC and SOPC mixed with 10% cholesterol. The behavior of all quantities shows that cholesterol alters the characteristics of SOPC lipid bilayer. Moreover, we found that the phase transition temperature of the SOPC membrane is shifted after mixing with cholesterol in agreement with experimental findings.

Active targeting is a prospective strategy for controlled drug delivery to malignant tumor tissues. One of the approaches relies on recognition of a bioactive ligand by a receptor expressed abundantly on the surface of cancer cell membranes. A promising ligand-receptor pair is folic acid (or its dianionic form, folate) combined with the folate receptor-α (FRα). A number of targeting drug delivery systems based on folate have been suggested, but the mechanism of binding of the ligand or its derivatives to the receptor is not fully known at the molecular level. The current study summarizes the results from unbiased all-atom molecular dynamics simulations at physiological conditions describing the binding of two forms of folate and four of its synthetically available derivatives to FRα. The models (ca. 185,000 atoms) contain one receptor molecule, embedded in the outer leaflet of a lipid bilayer, and one ligand, all immersed in saline. The bilayer represents a human cancer cell membrane and consists of 370 asymmetrically distributed lipid molecules from 35 types. The ability of the vector molecules to bind to the receptor, the position of binding, and the interactions between them are analyzed. Spontaneous binding on the nanosecond scale is observed for all molecules, but its time, position, and persistence depend strongly on the ligand. Only folate, 5-methyltetrahydrofolate, and raltitrexed bind selectively at the active site of the receptor. Two binding poses are observed, one of them (realized by raltitrexed) corresponding qualitatively to that reported for the crystallographic structure of the complex folate-FRα. Pemetrexed adsorbs nonspecifically on the protein surface, while methotrexate and pteroyl ornithine couple much less to the receptor. The molecular simulations reproduce qualitatively correctly the relative binding affinity measured experimentally for five of the ligands. Analysis of the interactions between the ligands and FRα shows that in order to accomplish specific binding to the active site, a combination of hydrogen bonding, π-stacking, and van der Waals and Coulomb attraction should be feasible simultaneously for the vector molecule. The reported results demonstrate that it is possible to observe receptor-ligand binding without applying bias by representing the local environment as close as possible and contain important molecular-level guidelines for the design of folate-based systems for targeted delivery of anticancer drugs.

The determination of the predominant tautomeric form of folate in solution is addressed theoretically and experimentally. OFT and atomistic molecular dynamics simulations are used to compare the most stable tautomers of folate. B3LYP/6-311+G(d) model chemistry shows that the lactam form of folate FA-N3 is the most energetically favorable tautomer. The lactam FA-N1 differs by about 2.5 kcal/mol. The conformation of the molecule does not influence markedly the energy ordering of the tautomers. Molecular dynamics results for the two lactams in saline outline similar behavior of the two molecules and flexible docking predicts comparable interactions with the folate receptor-alpha (FR-alpha). H-1 NMR spectra of folic acid in water and DMSO also identify the lactam tautomers as present in the solutions. Both H-1 and C-13 chemical shifts show fast exchange of protons between the N1 and N3 positions of pterin. (C) 2019 Elsevier B.V. All rights reserved.

Thorough computational description of the properties of membrane-anchored protein receptors, which are important for example in the context of active targeting drug delivery, may be achieved by models representing as close as possible the immediate environment of these macromolecules. An all-atom bilayer, including 35 different lipid types asymmetrically distributed among the two monolayers, is suggested as a model neoplastic cell membrane. One molecule of folate receptor-α (FRα) is anchored into its outer leaflet, and the behavior of the system is explored by atomistic molecular dynamics simulations. The total number of atoms in the model is ∼185 000. Three 1-μs-long simulations are carried out, where physiological conditions (310 K and 1 bar) are maintained with three different pressure scaling schemes. To evaluate the structure and the phase state of the membrane, the density profiles of the system, the average area per lipid, and the deuterium order parameter of the lipid tails are calculated. The bilayer is in liquid ordered state, and the specific arrangement varies between the three trajectories. The changes in the structure of FRα are investigated and are found time- and ensemble-dependent. The volume of the ligand binding pocket fluctuates with time, but this variation remains independent of the more global structural alterations. The latter are mostly "waving" motions of the protein, which periodically approaches and retreats from the membrane. The semi-isotropic pressure scaling perturbs the receptor most significantly, while the isotropic algorithm induces rather slow changes. Maintaining constant nonzero surface tension leads to behavior closest to the experimentally observed one.

Folate and its synthetic analogues, called antifolates, are known to have diverse bio-applications, for example as cell proliferation stimulators or anticancer drugs. Their molecular structure is important for performing the required biological activity. Since all folate-derived ligands contain a peptide-like amide bond, its configuration is one of the key components for the functional fitness of such compounds. During the modelling of folate and three of its derivatives - methotrexate, 5-methyl tetrahydrofolate, and pteroyl ornithine, we registered significant population of the cis isomers along the amide bond. The properties of the cis and trans forms of the ligands in saline are studied in detail by classical atomistic molecular dynamics and by quantum chemical methods. The calculations predict high probability for coexistence of the cis isomers for two of the ligands. The energetic instability of the cis form is explained with a σ-character admixture into the C[double bond, length as m-dash]O(π) bond, while its magnitude is attributed to the pattern of local electron density redistribution. The cis forms of all molecules have markedly slower structural dynamics than the trans ones, which might affect their behavior in vivo.

The study is focused on description of folate and several antifolates at physiological conditions. Knowledge of the molecular structure and dynamics is important for understanding their biological activity and therapeutic application. They are modelled in saline by atomistic molecular dynamics simulations and characterized in detail. In addition, quantum chemical calculations are used for determining the electronic structure of the six compounds. All molecules are highly flexible and have similar interactions with water. Specifics are found in some of their local backbone conformations, in the molecular shape, and in the electron density distribution. Most of the ligands have fairly folded geometry and prefer U- and Z-shapes. Two of them are quasi-linear. Key to the molecular shape are the bicyclic fragment, its bridge, and the charge of the terminal amino acid residue. Docking into the active site of folate receptor-α predicts a similar best binding pose for four of the ligands, which requires stretching of pterin and bending of glutamate/ornithine relative to the geometry in saline. The chemical modifications in the antifolates induce local electron density redistribution in comparison to folate, leading to increase of the positive charges of the neighboring fragments. The obtained results would help better tuning of the potential usage of the molecules in new bioactive materials, e.g., as vector-ligands for drug delivery.