Sergey Valer'Evich Panteleev

The properties of subnanosized metal clusters are of great interest, since they exhibit high activity in catalysis and can serve as an elemental base for nanoelectronics or quantum computing technologies. For such applications, a fundamentally important issue is the possibility of size- and structure-selective synthesis of clusters, which is largely determined by the number and energy distribution of their isomers, as well as the energy barriers to their rearrangements. Thus, the lifetimes and rates of rearrangement of isomers of subnanosized clusters is an urgent problem of both physicochemical theory and practical applications. Earlier, the complete set of magnesium cluster isomers was found in the course of global DFT optimization with subsequent optimization at the MP2/cc-pVQZ and CCSD(T)/cc-pVQZ levels. In this paper, we study the structural rearrangements of these isomers on the DFT PES by searching for transition states of their structural rearrangements and by the ADMP ab initio molecular dynamics simulation of their time evolution. The ADMP trajectory length was up to 50 ps with a step of 0.2 fs at temperatures from 300 to 700 K. The trajectories were analyzed using a specially developed algorithm for assigning trajectory points to the reference isomer structures. Based on this assignment, the average lifetimes, rearrangement probabilities, and average ratios of isomers in the equilibrium mixture were established. It is shown that the most kinetically stable structures are the Mg₉ and Mg₁₀ clusters. In contrast, other clusters at 300-400 K contain a noticeable admixture of isomeric structures.

A two-stage GridSearch combined with active learning was employed to optimize GAP model parameters for Mg clusters, enabling reliable structural predictions in the extrapolative domain Mg_n, n > 50.

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.

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.

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.

About 9000 structures of magnesium clusters Mg_n (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 n^8.9, whereas GP potential results in the n^4.3 dependence.

Fossil fuel oxy-combustion is an emergent technology where 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 sCO2 environment is predicted at 30-1000 atm and 1000-2000 K. We adopt multiscale approach, where reactive complex is treated quantum mechanically in rigid rotor/harmonic oscillator approximation, while environment effects at different densities are taken into account by 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 bias potential. Multi-state empirical valence bond model is applied to describe free radical formation accurately at the cost of classical force field. Predicted rates at low densities agree well with the literature data. Rate constants at 300 atm is 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.

The development of antidotes to organophosphate poisons is an important aspect of modern pharmacology. Recombinant acetylcholinesterase and butyrylcholinesterase are effective DNA-encoded acceptors of organophosphate poisons and, in particular, pesticides. Here, we present the results of a study on the effectiveness of recombinant butyrylcholinesterase (BChE) in modeling organophosphate poisoning caused by oral administration of paraoxon at a dose of 2 mg / kg. The study showed a high activity of BChE as a protective agent for subchronic anticholinesterase poisoning in an in vivo model. The administration of BChE in a dose of 20 mg / kg allows one to avoid mortality, and also contributed to rapid recovery after model poisoning.