The anti-hypertensive drugs amlodipine, atenolol and lisinopril, in ordinary and PEGylated forms, with different combined-ratios, were studied by molecular dynamics simulations using GROMACS software. Twenty simulation systems were designed to evaluate the interactions of drug mixtures with a dimyristoylphosphatidylcholine (DMPC) lipid bilayer membrane, in the presence of water molecules. In the course of simulations, various properties of the systems were investigated, including drug location, diffusion and mass distribution in the membrane; drug orientation; the lipid chain disorder as a result of drug penetration into the DMPC membrane; the number of hydrogen bonds; and drug surface area. According to the results obtained, combined drugs penetrate deeper into the DMPC lipid bilayer membrane, and the lipid chains remain ordered. Also, the combined PEGylated drugs, at a combination ratio of 1:1:1, enhance drug penetration into the DMPC membrane, reduce drug agglomeration, orient the drug in a proper angle for easy penetration into the membrane, and decrease undesirable lipotoxicity due to distorted membrane self-assembly and thickness.
In order to understand the interaction between naratriptan and a fully hydrated bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyl-choline (POPC), we carried out molecular dynamics simulations. The simulations were performed considering neutral and protonated ionization states, starting from different initial conditions. At physiological pH, the protonated state of naratriptan is predominant. It is expected that neutral compounds could have larger membrane partition than charged compounds. However, for the specific case of triptans, it is difficult to study neutral species in membranes experimentally, making computer simulations an interesting tool. When the naratriptan molecules were originally placed in water, they partitioned between the bilayer/water interface and water phase, as has been described for similar compounds. From this condition, the drugs displayed low access to the hydrophobic environment, with no significant effects on bilayer organization. The molecules anchored in the interface, due mainly to the barrier function of the polar and oriented lipid heads. On the other hand, when placed inside the bilayer, both neutral and protonated naratriptan showed self-aggregation in the lipid tail environment. In particular, the protonated species exhibited a pore-like structure, dragging water through this environment.
Molecular dynamics simulations were performed to investigate the separation of trihalomethanes (THMs) from water using boron nitride nanosheets (BNNSs). The studied systems included THM molecules and a functionalized BNNS membrane immersed in an aqueous solution. An external pressure was applied to the z axis of the systems. Two functionalized BNNSs with large fluorinated-hydrogenated pore (F-H-pores) and small hydrogen-hydroxyl pore (H-OH-pores) were used. The pores of the BNNS membrane were obtained by passivating each nitrogen and boron atoms at the pore edges with fluorine and hydrogen atoms in the large pore or with hydroxyl and hydrogen atoms in the small pore. The results show that the BNNS with a small functionalized pore was impermeable to THM molecules, in contrast to the BNNS with a large functionalized pore. Using these membranes, water contaminants can be removed at lower cost.
Graphical Abstract A snapshot of the simulation system. The BNNS membrane with the large functionalized pore is located in the middle of the box. The size of the box is 3 × 3 × 5 nm3. Green chlorine, cyan carbon, red oxygen, white hydrogen
In the present work we investigated the differential interactions of the antimicrobial peptides (AMPs) aurein 1.2 and maculatin 1.1 with a bilayer composed of a mixture of the lipids 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (POPG) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE). We carried out molecular dynamics (MD) simulations using a coarse-grained approach within the MARTINI force field. The POPE/POPG mixture was used as a simple model of a bacterial (prokaryotic cell) membrane. The results were compared with our previous findings for structures of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), a representative lipid of mammalian cells. We started the simulations of the peptide–lipid system from two different initial conditions: peptides in water and peptides inside the hydrophobic core of the membrane, employing a pre-assembled lipid bilayer in both cases. Our results show similarities and differences regarding the molecular behavior of the peptides in POPE/POPG in comparison to their behavior in a POPC membrane. For instance, aurein 1.2 molecules can adopt similar pore-like structures on both POPG/POPE and POPC membranes, but the peptides are found deeper in the hydrophobic core in the former. Maculatin 1.1 molecules, in turn, achieve very similar structures in both kinds of bilayers: they have a strong tendency to form clusters and induce curvature. Therefore, the results of this study provide insight into the mechanisms of action of these two peptides in membrane leakage, which allows organisms to protect themselves against potentially harmful bacteria.
Graphical Abstract Aurein pore structure (green) in a lipid bilayer composed by POPE (blue) and POPG (red) mixture. It is possible to see water beads (light blue) inside the pore.
Coarse-grained dynamical simulations have been performed to investigate the behavior of a surfactant micelle in the presence of six different alcohols: hexanol, octanol, decanol, dodecanol, tetradecanol, and hexadecanol. The self-assembly of sodium dodecyl sulfate (SDS) is modified by the alcohol molecules into cylindrical and bilayer micelles as a function of the alcohol/SDS mass ratio. Therefore, in order to understand, from a molecular point of view, how SDS and alcohol molecules self-organize to form the new micelles, different studies were carried out. Analysis of micelle structures, density profiles, and parameters of order were conducted to characterize the shape and size of those micelles. The density profiles revealed that the alcohol molecules were located at the water–micelle interface next to the SDS molecules at low alcohol/SDS mass ratio. At high alcohol/SDS mass ratios, alcohol molecules moved to the middle of the micelle by increasing their size and by producing a structural change. Moreover, micelle structures and sizes were influenced not only by the alcohol/SDS mass ratio but also by the order of the SDS and alcohol tails. Finally, the size of the micelles and enthalpy calculations were used as order parameters to determine a structural phase diagram of alcohol/SDS mixtures in water.
Cardiotoxins (CTXs) belonging to the three-finger toxin superfamily of snake venoms are one of principal toxic components and the protein toxins exhibit membrane lytic activities when the venoms are injected into victims. In the present study, complex formations between CTX VI (a P-type CTX from Naja atra) and CTX1 (an S-type CTX from Naja naja) on zwitterionic POPC bilayers (a major lipid component of cell membranes) have been studied in near physiological conditions for a total dynamic time scale of 1.35 μs using all-atom molecular dynamics (MD) simulations. Comprehensive analyses of the MD data revealed that residues such as Leu1, Lys2, Tyr11, Lys31, Asp57 and Arg58 of CTX VI, and Ala16, Lys30 and Arg58 of CTX1 were crucial for establishing interactions with the POPC bilayer. Moreover, loop I, along with globular head and loop II of CTX VI, and loop II of CTX1 were found to be the structural regions chiefly governing complex formation of the respective proteins with POPC. Rationalizations for the differential binding modes of CTXs and implications of the findings for designing small molecular inhibitors to the toxins are also discussed.
Bond critical points (BCPs) in the quantum theory of atoms in molecules (QTAIM) are shown to be a consequence of the molecular topology, symmetry, and the Poincaré-Hopf relationship, which defines the numbers of critical points of different types in a scalar field. BCPs can be induced by a polarizing field or by addition of a single non-bonded atom to a molecule. BCPs and their associated bond paths are therefore suggested not to be a suitable means of identifying chemical bonds, or even attractive intermolecular interactions.
The human respiratory syncytial virus (hRSV) is the major cause of lower respiratory tract infection in children and elderly people worldwide. Its genome encodes 11 proteins including SH protein, whose functions are not well known. Studies show that SH protein increases RSV virulence degree and permeability to small compounds, suggesting it is involved in the formation of ion channels. The knowledge of SH structure and function is fundamental for a better understanding of its infection mechanism. The aim of this study was to model, characterize, and analyze the structural behavior of SH protein in the phospholipids bilayer environment. Molecular modeling of SH pentameric structure was performed, followed by traditional molecular dynamics (MD) simulations of the protein immersed in the lipid bilayer. Molecular dynamics with excited normal modes (MDeNM) was applied in the resulting system in order to investigate long time scale pore dynamics. MD simulations support that SH protein is stable in its pentameric form. Simulations also showed the presence of water molecules within the bilayer by density distribution, thus confirming that SH protein is a viroporin. This water transport was also observed in MDeNM studies with histidine residues of five chains (His22 and His51), playing a key role in pore permeability. The combination of traditional MD and MDeNM was a very efficient protocol to investigate functional conformational changes of transmembrane proteins that act as molecular channels. This protocol can support future investigations of drug candidates by acting on SH protein to inhibit viral infection.
Coarse-grained force field (CGFF) methods were applied to study the self-assembly of sodium dodecyl sulfate with fragrance additives. The CGFF parameters were parameterized and validated using experimental and all-atom simulation data. Direct molecular dynamics simulations were carried out to characterize the initial aggregation, partitioning of fragrances, and chemical potentials of the surfactant and fragrance molecules in aggregates of different sizes. The equilibrium critical micelle concentrations (CMCs) and micelle size distributions, which could not be obtained by direct simulation, were predicted using the calculated chemical potentials in combination with a thermodynamic model. The predicted partitioning of fragrances, CMCs, micelle sizes, and micelle structures agree well with previously reported experimental data.
In this work, we address the effects of molecular doping on the electronic properties of fluorinated and chlorinated silicon nanowires (SiNWs), in comparison with those corresponding to hydrogen-passivated SiNWs. Adsorption of n-type dopant molecules on hydrogenated and halogenated SiNWs and their chemisorption energies, formation energies, and electronic band gap are studied by using density functional theory calculations. The results show that there are considerable charge transfers and strong covalent interactions between the dopant molecules and the SiNWs. Moreover, the results show that the energy band gap of SiNWs changes due to chemical surface doping and it can be further tuned by surface passivation. We conclude that a molecular based ex-situ doping, where molecules are adsorbed on the surface of the SiNW, can be an alternative path to conventional doping.
Catalytic fields illustrate topology of the optimal charge distribution of a molecular environment reducing the activation energy for any process involving barrier crossing, like chemical reaction, bond rotation etc. Until now, this technique has been successfully applied to predict catalytic effects resulting from intermolecular interactions with individual water molecules constituting the first hydration shell, aminoacid mutations in enzymes or Si→Al substitutions in zeolites. In this contribution, hydrogen to fluorine (H→F) substitution effects for two model reactions have been examined indicating qualitative applicability of the catalytic field concept in the case of systems involving intramolecular interactions.
In this study, the doped defects in nitromethane crystals were investigated using first-principles calculations for the first time. We introduce dopant atoms in the interstitial sites of the nitromethane lattice, aiming to study the effects of element-doping on the structural properties, electronic properties, and sensitivity characteristics. The obtained results show that doped defects obviously affect the neighboring nitromethane molecules. The modification of electronic properties shows that the band gaps are significantly influenced by doped defects. Partial density of states and population analysis further reveal the mechanism for sensitivity control of nitromethane. It is shown that the new electronic states were introduced in the forbidden bands and the doped defects resulted in charge redistributions in the systems.
Using density functional theory (DFT) and molecular dynamics (MD), we studied the interaction of a titanium atom with a half of a C60 fullerene (i.e., C30), formed from the corannulene structure with a pentagonal base. We considered atmospheric pressure and 300 K. We found that the most stable adsorption of the titanium atom on C30 occurs in the concave surface of the molecule. Afterward, we investigated the interaction of the system C30-titanium with carbon monoxide and carbon dioxide molecules, respectively. We found that each of these molecules is chemisorbed, with no dissociation. The value of the adsorption energy for the carbon monoxide molecule varies from ?0.897 to ?1.673 eV, and for the carbon dioxide molecule, it is between ?1.065 and ?1.274 eV. These values depend on the initial orientation of these molecules with respect to TiC30.
The structure and stability of various ternary complexes in which an extended aromatic system such as coronene interacts with ions/atoms/molecules on opposite faces of the π-electron cloud were investigated using ab initio calculations. By characterizing the nature of the intermolecular interactions using an energy decomposition analysis, it was shown that there is an interplay between various types of interactions and that there are co-operativity effects, particularly when different types of interactions coexist in the same system.
Graphical abstract Weak OH-π, π-π and van der Waals-π ternary systems are stabilized through dispersion interactions. Cation-π ternary systems are stabilized by through-space electrostatic interactions.
Ionic liquids (ILs) constitute a fast growing class of compounds finding multiple applications in science and technology. Morpholinium-based ILs (MBILs) and their mixtures with polar molecular co-solvents are interesting as sustainable electrolyte systems for electrochemistry. We investigate local structures of protic and apropic morpholinium cations in acetonitrile (ACN) using semi-empirical molecular dynamics (MD) simulations. An impact of an anion (acetate) on the cation solvation regularities is discussed. Unlike oxygen, nitrogen of the morpholine ring is a strong electrophilic binding center. This site is responsible for the interactions of the cation with the solvent and with the anion. In protic MBILs, the role of nitrogen is delegated to the proton, which is linked to nitrogen. The acetate anion weakens solvation of the cation due to occupation of space near nitrogen or proton. The analysis reveals a favorable solvation of MBILs in ACN, which is a prerequisite for a new high-performance electrolyte system. The reported structural data were validated through point-to-point comparison with the MP2 post-Hartree-Fock theory and density functional theory.
In this article, we explore, both theoretically and experimentally, the general reactivity of alkyl hydrogeno-phenylphosphinates with alcohols. We show that alcohol molecules act exclusively as nucleophilic species, and add to alkyl hydrogeno-phenylphosphinates, leading to pentacoordinated intermediates. These intermediates are shown to subsequently competitively undergo alcohol eliminations and/or Berry pseudorotations. This offers several possible routes for racemizations and/or alcohol exchange reactions. Transition standard Gibbs free energies predicted from DFT calculations for the overall alcohol exchange mechanism are shown to be compatible with those experimentally measured in case ethanol reacts with ethyl hydrogeno-phenylphosphinate (134.5～136.0 kJ mol?1 at 78 °C).
In this article, we explore the capacity of formed Schiff base complexes to trap metal atoms or ions, using their aromatic ends. The intrinsic geometry of each complex defines the process of substitution. Two cases were studied; one involving a trans Schiff base complex and the other considering how a salen ligand, with nickel systems traps chromium. We also assessed the nature of the new bonds and the frontier molecular orbitals.
The correlation between the kinetic stability of molecules against temperature and variations in their geometric structure under optical excitation is investigated by the example of different organic pheromone molecules sensitive to temperature or ultraviolet radiation using the density functional theory. The kinetic stability is determined by the previously developed method based on the calculation of the probability of extension of any structural bond by a value exceeding the limit value Lмах corresponding to the breaking of the bond under temperature excitation. The kinetic stability calculation only requires the eigenfrequencies and vibrational mode vectors in the molecule ground state to be calculated, without determining the transition states. The weakest bonds in molecules determined by the kinetic stability method are compared with the bond length variations in molecules in the excited state upon absorption of light by a molecule. Good agreement between the results obtained is demonstrated and the difference between them is discussed. The universality of formulations within both approaches used to estimate the stability of different pheromone molecules containing strained cycles and conjugated, double, and single bonds allows these approaches to be applied for studying other molecules.
Protonation in the two-electron/two-proton reduction processes of 2,6-dichlorophenolindophenolate (DCIP) is investigated combining density functional theory (DFT) and molecular dynamics (MD) methods. DCIP (anion), DCIP?– (radical anion), and DCIP2? (dianion) are considered, including the electronic structure analysis from the prospective of quantum theory of atoms and molecules (QTAIM). It is shown that oxygen on the indophenolate moiety and nitrogen are the first and/or the second proton acceptor sites and their energetic order depends on the total charge of the system. MD simulations of differently charged species interacting with the solvent molecules have been performed for methanol, water, and oxonium cation (H3O+). Methanol and water molecules are found to form only hydrogen bonds with the solute irrespective of its charge. The calculated pKa values show that the imino group of DCIPH? is a weaker acid than water. While in the case of DCIP (and DCIP?–) plus oxonium cation, proton transfer from the solvent to the solute was evidenced for both aforementioned acceptor sites. In addition, MD simulations of bulks containing 15 and 43 molecules of water around the DCIP molecule have been performed, revealing the formation of 2–4 hydrogen bonds.
Graphical Abstract 2,6-Dichlorophenolindophenolate interacts with solvent molecules (water, oxonium cation and methanol). Hydrogen transfer and electronic structure are studied by DFT and molecular dynamics methods
