Lipid II as a Target for Novel Antibiotics:Structural and Molecular Dynamics Studies.
The growing problem of antibiotic resistance in medicine raises the attention to antimicrobial substances that act on non-protein molecules, which have more conservative structure comparing to proteins or peptides. One of the most promising and studied targets is lipid II — the participant of the bacterial cell wall biosynthetic pathway. Lipid II is present in the bacterial membrane only and has a conservative chemical structure. There are several classes of natural antibiotics acting on lipid II, some of which block the peptidoglycan synthesis by formation of a strong complex with lipid II, and others have an additional bactericidal mechanism involved a violation of the membrane integrity. This review examines the prospects for using such antibacterial substances as new drugs to combat antibiotic-resistant pathogens. The main emphasis is made on the studies of membrane-embedded lipid II structure and molecular mechanisms of its recognition by water-soluble antibiotics, and also on computer modelling of their interaction.
How is a water-soluble globular protein able to spontaneously cross a cellular membrane? It is commonly accepted that it undergoes significant structural rearrangements on the lipid-water interface, thus acquiring membrane binding and penetration ability. In this study molecular dynamics (MD) simulations have been used to explore large-scale conformational changes of the globular viscumin A chain in a complex environment – comprising urea and chloroform/methanol (CHCl3/MeOH) mixture. Being well-packed in aqueous solution, viscumin A undergoes global structural rearrangements in both organic media. In urea, the protein is “swelling” and gradually loses its long-distance contacts, thus resembling the “molten globule” state. In CHCl3/MeOH, viscumin A is in effect turned “inside out”. This is accompanied with strengthening of the secondary structure and surface exposure of hydrophobic epitopes originally buried inside the globule. Resulting solvent-adapted models were further subjected to Monte Carlo simulations with an implicit hydrophobic slab membrane. In contrast to only a few point surface contacts in water and two short regions with weak protein-lipid interactions in urea, MD-derived structures in CHCl3/MeOH reveal multiple determinants of membrane interaction. Consequently it is now possible to propose a specific pathway for the structural adaptation of viscumin A with respect to the cell membrane – a probable first step of its translocation into cytoplasmic targets.
Although the high-pressure phase diagram of carbon at extreme temperatures and pressures is in focus of theoretical and experimental dynamic compression studies, there still exist outstanding problems including disagreement between theoretical predictions and experiments. Using first-principles molecular dynamics simulations at high temperatures and pressures and employing large unit cells, we construct an accurate phase diagram of carbon using two-phase and Z-methods. In accord with previous simulations, a large positive slope of the melting line is observed for pressures from 0 to 200 GPa, whereas at pressures above 500 GPa a very small negative slope exists, which is in contrast to most of previous simulations and experiment. Our accurate results demonstrate the necessity for future dynamic compression experiments to clarify behavior of carbon at extreme conditions including its melting line.
Due to their high durability and immobilization properties, cementitious materials have found a considerable application in the design and construction of radioactive waste repositories in the last decades. During cement paste production, organic additives are introduced to modify various properties of cement. The presence of such organic complexants may negatively affect the immobilizing properties of cement with respect to radionuclides. For better understanding and prediction of the effects of interactions between organic molecules and cementitious materials with radionuclides, we have developed several representative models consisting of three principal components: (i) calcium silicate hydrate (C-S-H) phase - the main binding phase of cement; (ii) gluconate, a simple well-described molecule, as a representative of organic additives; (iii) U(VI), as one of the most studied radionuclides of the actinide series. The C-S-H phase with low Ca/Si ratio (~0.83) typical for â€œlow-pHâ€ and degraded cement pastes has been selected for this modelling study. Structural, and energetic aspects of the sorption processes of uranyl, gluconate, and their mutual correlations on the surface of cement were quantitatively modeled by classical molecular dynamics (MD) and potential of mean force (PMF) calculations. The ternary surface complex formation between uranyl hydroxides and Ca2+ cations at the C-S-H aqueous interfaces is shown to have an important role in the overall sorption process. In the presence of gluconate, U(VI) sorption on C-S-H is facilitated by weakening the Ca2+ binding with the surface. Additionally, Na+ is proven to be an important competitor for certain surface sorption sites and can potentially affect the equilibrium properties of the interface.
The dynamics of a two-component Davydov-Scott (DS) soliton with a small mismatch of the initial location or velocity of the high-frequency (HF) component was investigated within the framework of the Zakharov-type system of two coupled equations for the HF and low-frequency (LF) fields. In this system, the HF field is described by the linear Schrödinger equation with the potential generated by the LF component varying in time and space. The LF component in this system is described by the Korteweg-de Vries equation with a term of quadratic influence of the HF field on the LF field. The frequency of the DS soliton`s component oscillation was found analytically using the balance equation. The perturbed DS soliton was shown to be stable. The analytical results were confirmed by numerical simulations.
Radiation conditions are described for various space regions, radiation-induced effects in spacecraft materials and equipment components are considered and information on theoretical, computational, and experimental methods for studying radiation effects are presented. The peculiarities of radiation effects on nanostructures and some problems related to modeling and radiation testing of such structures are considered.