Temperature-Induced Restructuring of Mycolic Acid Bilayers Modeling the Mycobacterium tuberculosis Outer Membrane: A Molecular Dynamics Study.

The emergence of new drug-resistant strains of the tuberculosis pathogen Mycobacterium tuberculosis (Mtb) is a new challenge for modern medicine. Its resistance capacity is closely related to the properties of the outer membrane of the Mtb cell wall, which is a bilayer membrane formed by mycolic acids (MAs) and their derivatives. To date, the molecular mechanisms of the response of the Mtb outer membrane to external factors and, in particular, elevated temperatures have not been sufficiently studied. In this work, we consider the temperature-induced changes in the structure, ordering, and molecular mobility of bilayer MA membranes of various chemical and conformational compositions. Using all-atom long-term molecular dynamics simulations of various MA membranes, we report the kinetic parameters of temperature-dependent changes in the MA self-diffusion coefficients and conformational compositions, including the apparent activation energies of these processes, as well as the characteristic times of ordering changes and the features of phase transitions occurring over a wide range of elevated temperatures. Understanding these effects could be useful for the prevention of drug resistance and the development of membrane-targeting pharmaceuticals, as well as in the design of membrane-based materials.

Free Energy Barriers for Passive Drug Transport through the Mycobacterium tuberculosis Outer Membrane: A Molecular Dynamics Study.

The emergence of multi-drug-resistant tuberculosis strains poses a significant challenge to modern medicine. The development of new antituberculosis drugs is hindered by the low permeability of many active compounds through the extremely strong bacterial cell wall of mycobacteria. In order to estimate the ability of potential antimycobacterial agents to diffuse through the outer mycolate membrane, the free energy profiles, the corresponding activation barriers, and possible permeability modes of passive transport for a series of known antibiotics, modern antituberculosis drugs, and prospective active drug-like molecules were determined using molecular dynamics simulations with the all-atom force field and potential of mean-force calculations. The membranes of different chemical and conformational compositions, density, thickness, and ionization states were examined. The typical activation barriers for the low-mass molecules penetrating through the most realistic membrane model were 6-13 kcal/mol for isoniazid, pyrazinamide, and etambutol, and 19 and 25 kcal/mol for bedaquilin and rifampicin. The barriers for the ionized molecules are usually in the range of 37-63 kcal/mol. The linear regression models were derived from the obtained data, allowing one to estimate the permeability barriers from simple physicochemical parameters of the diffusing molecules, notably lipophilicity and molecular polarizability.

Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane.

Bilayers of mycolic acids (MAs) form the outer membrane of Mycobacterium tuberculosis that has high strength and extremely low permeability for external molecules (including antibiotics). For the first time, we were able to study them using the all-atom long-term molecular dynamic simulations (from 300 ns up to 1.2 µs) in order to investigate the conformational changes and most favorable structures of the mycobacterial membranes. The structure and properties of the membranes are crucially dependent on the initial packing of the α-mycolic acid (AMA) molecules, as well as on the presence of the secondary membrane components, keto- and methoxy mycolic acids (KMAs and MMAs). In the case of AMA-based membranes, the most labile conformation is W while other types of conformations (sU as well as sZ, eU, and eZ) are much more stable. In the multicomponent membranes, the presence of the KMA and MMA components (in the W conformation) additionally stabilizes both the W and eU conformations of AMA. The membrane in which AMA prevails in the eU conformation is much thicker and, at the same time, much denser. Such a packing of the MA molecules promotes the formation of a significantly stronger outer mycobacterial membrane that should be much more resistant to the threatening external factors.

How Many Isomers Do Metallic Clusters Have? Case of Magnesium Clusters of up to 55 Atoms.

About 9000 structures of magnesium clusters Mgn (n = 2-13) generated via different methods were optimized at the DFT levels in order to estimate the number of all possible stable structures that can exist for the given cluster size (∼820,000 PES points were explored in total). It was found that the number of possible cluster isomers N quickly grows with a number of atoms n; however, it is significantly lower than the number of possible nonisomorphic graph structures, which can be drawn for the given n. At the DFT potential energy surface, we found only 543 local minima corresponding to the isomers of Mg2-Mg13. The number of isomers obtained in the DFT optimizations grows with n approximately as n4, whereas the N values extrapolated to the infinite generation process grow as n8. The cluster geometries obtained from the global DFT optimization were then used to adjust two empirical potentials of Gupta type (GP) and modified Sutton-Chen type (SCG3) describing the interactions between the magnesium atoms. Using these potentials, the extensive sets of structures Mg2-Mg55 (up to 30,000 clusters for each n) were optimized to obtain the dependence of the cluster isomer count on n in the continuous range of n = 2-30 and for selected n up to n = 55. It was found that the SCG3 potential, which is closer to the DFT results, gives a number of possible isomers growing as approximately n8.9, whereas GP potential results in the n4.3 dependence.

Molecular Dynamics of Combustion Reactions in Supercritical Carbon Dioxide. Part 5: Computational Study of Ethane Dissociation and Recombination Reactions C2H6 ⇌ CH3 + CH3.

Fossil fuel oxy-combustion is an emerging technology where the habitual nitrogen diluent is replaced by high-pressure supercritical CO2 (sCO2), which increases the efficiency of energy conversion. In this study, the chemical kinetics of the combustion reaction C2H6 ⇌ CH3 + CH3 in the sCO2 environment is predicted at 30-1000 atm and 1000-2000 K. We adopt a multiscale approach, where the reactive complex is treated quantum mechanically in rigid rotor/harmonic oscillator approximation, while environment effects at different densities are taken into account by the potential of mean force, produced with classical molecular dynamics (MD). Here, we used boxed MD, where enhanced sampling of infrequent events of barrier crossing is accomplished without application of the bias potential. The multistate empirical valence bond model is applied to describe free radical formation accurately at the cost of the classical force field. Predicted rates at low densities agree well with the literature data. Rate constants at 300 atm are 2.41 × 1014 T-0.20 exp(-77.03 kcal/mol/ RT) 1/s for ethane dissociation and 8.44 × 10-19 T1.42 exp(19.89 kcal/mol/ RT) cm3/molecule/s for methyl-methyl recombination.

Molecular dynamics of combustion reactions in supercritical carbon dioxide. Part 4: boxed MD study of formyl radical dissociation and recombination.

Fossil fuel oxy-combustion is an emergent technology where habitual nitrogen diluent is replaced by high pressure (supercritical) carbon dioxide. The supercritical state of CO2 increases the efficiency of the energy conversion and the absence of nitrogen from the reaction mixture reduces pollution by NOx. However, the effects of a supercritical environment on elementary reactions kinetics are not well understood at present. We used boxed molecular dynamics simulations at the QM/MM theory level to predict the kinetics of dissociation/recombination reaction HCO• + [M] ↔ H• + CO + [M], an important elementary step in many combustion processes. A wide range of temperatures (400-1600 K) and pressures (0.3-1000 atm) were studied. Potentials of mean force were plotted and used to predict activation free energies and rate constants. Based on the data obtained, extended Arrhenius equation parameters were fitted and tabulated. The apparent activation energy for the recombination reaction becomes negative above 30 atm. As the temperature increased, the pressure effect on the rate constant decreased. While at 400 K the pressure increase from 0.3 atm to 300 atm accelerated the dissociation reaction by a factor of 250, at 1600 K the same pressure increase accelerated this reaction by a factor of 100. Graphical abstract Formyl radical surrounded by carbon dioxide molecules.

Molecular Dynamics Study of Combustion Reactions in Supercritical Environment. Part 3: Boxed MD Study of CH3 + HO2 → CH3O + OH Reaction Kinetics.

The kinetics of reaction CH3 + HO2 → CH3O + OH in supercritical carbon dioxide media at pressures from 0.3 to 1000 atm in the temperature range (600-1600) K was studied using boxed molecular dynamics simulations at QM/MM theory level with periodical boundary conditions. The mechanism of this process includes two consecutive steps: formation and decomposition of CH3OOH intermediate. We calculated the activation free energies and rate constants of each step, then used Bodenstein's quasistationary concentrations approximation to estimate the rate constants of the reaction. On the basis of the temperature dependence of the rate constants, parameters in the extended Arrhenius equation were determined. We found that reaction rate of each step, as well as overall reaction, increases with increasing CO2 pressure in the system. The most effective zone for the process is T = 1000-1200 K, and the CO2 pressure is about 100 atm.

Molecular Dynamics Study of Combustion Reactions in a Supercritical Environment. Part 2: Boxed MD Study of CO + OH → CO2 + H Reaction Kinetics.

Oxy-fuel combustion technology holds a great promise in both increasing the efficiency of the energy conversion and reducing environmental impact. However, effects of the higher pressures and replacement of the nitrogen with carbon dioxide diluent are not well understood at present. The title reaction is one of the most important processes in combustion. Despite numerous studies, the effects of supercritical carbon dioxide environment did not receive much attention in the past. Here we report the results of boxed molecular dynamics simulations of these effects at QM/MM theory level with periodical boundary conditions. The free energy barriers for HOCO intermediate formation and decomposition were tabulated in a wide range of pressures (1-1000 atm) and temperatures (400-1600 K). Pressure dependence of calculated rate constants for these reaction steps and overall reaction were analyzed. We found that the CO2 environment may increase these rate constants up to a factor of 25, at near critical conditions. At higher temperatures, this effect weakens significantly. Numerical values for parameters of extended Arrhenius equation, suitable for combustion kinetic modeling are reported.