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.
Shear viscosity is one of the key subjects of molecular modeling studies since this quality is used in the development of lubricants. In this paper, we use molecular dynamics methods to predict viscosity dependence on pressure up to 1000 MPa for 2,2,4-trimethylhexane. The COMPASS class II force field is used to determine atomic interactions in the model. The shear viscosity is calculated using Green-Kubo and Müller-Plathe methods. To achieve the convergence of the Green-Kubo integral, the time decomposition method is used. The approach is validated by 2,2,4-trimethylpentane for which experimental data are available. The calculated 2,2,4-trimethylhexane viscosity coefficient dependence is fit by Tait-like equation and does not show super-Arrhenius behavior. The Tait fit matches the experiment produced by Scott Bair for the pressures up to 500 MPa within the accuracy of the methods.
Atomistic aspects of the structural organization, dynamics, and functioning of hydrated lipid bilayers - model cell membranes - are primarily governed by the fine balance of intermolecular interactions between all constituents of these systems. Besides the hydrophobic effect, which shapes the overall skeleton of lipid membranes, very important contribution to their behavior is made by hydrogen bonds (H-bonds) between lipid head groups. The latter determine such crucial phenomena in cell membranes, like dynamic ultra-nanodomain organization, hydration, fine-tuning of microscopic physico-chemical properties that allow the membrane to adapt quickly when binding/insertion external agents (proteins, etc.) The characteristics of such H-bonds (strength, spatial localization, etc.) dramatically depend on the local polarity properties of the lipid-water environment. In this work, we calculated free energies of H-bonded complexes between typical donor (NH3+, NH, OH) and acceptor (C=O, OH, COO-, COOH) groups of lipids in vacuo and in a set of explicit solvents with dielectric constants (ε) from 1 to 78.3, which mimic membrane environment at different depth. This was done using Monte Carlo simulations and an assessment of the corresponding Potential of Mean Force profiles. The strongest H-bonded complexes were observed in the nonpolar environment and their strength increased sharply with decreasing ε below 17. When ε changed, the largest free energy gain (> 10.8 kcal/mol) was observed for pairs of acceptors C=O and O(H) with donor NH3+. The complexation of the same acceptors with NH-donor in this range of ε was rather less sensitive to the environmental polarity: by ~1.5 kcal/mol. Dielectric-dependent interactions of polar lipid groups with water were evaluated as well. The results explain the delicate balance that determines the unique pattern of H-bonds for a particular lipid bilayer. Understanding the factors that regulate the propensity to H-bonding in lipid bilayers provides a fundamental basis for the rational design of new membrane nano-objects with predefined properties.
Solvation effects play a key role in chemical and biological processes. The microscopic properties of water near molecular surfaces are radically different from those in the bulk. Furthermore, behavior of water in confined volumes of nanometer scale, including transmembrane pores of ion channels, is especially nontrivial. Knowledge at the molecular level of structural and dynamic parameters of water in such systems is necessary to understand the mechanisms of ion channels functioning. In this work, the results of molecular dynamics (MD) simulations of water in the pore and selectivity filter domains of TRPV1 membrane channel are considered. These domains represent nanoscale volumes with strongly amphiphilic walls, where physical behavior of water radically differs from that of free hydration (e.g., at protein interfaces) or in the bulk. Inside the pore and filter domains, water reveals very heterogeneous spatial distribution and unusual dynamics: it forms compact areas localized near polar groups of particular residues. Residence time of water molecules in such areas is at least 1.5-3 times larger than that observed for similar groups at the protein surface. Presumably, these water “blobs” play an important role in functional activity of TRPV1. In particular, they take a part in hydration of the hydrophobic TRPV1 pore by localizing up to 6 waters near the so-called “lower gate” of the channel and reducing by this way the free energy barrier for ion and water transport. Although the channel is formed by four identical protein subunits, which are symmetrically packed in the initial experimental 3D structure, in the course of MD simulations, hydration of the same amino acid residues of individual subunits may differ significantly. This greatly affects the microscopic picture of the distribution of water in the channel and, potentially, the mechanism of its functioning. Therefore, reconstruction the full picture of the TRPV1 channel solvation requires a thorough atomistic simulations and analysis. It is important that the naturally occurred porous volumes like ion conducting protein domains reveal much more sophisticated and fine-tuned regulation of solvation than, e.g. artificially designed carbon nanotubes.
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.
By using superconducting quantum interference device (SQUID) magnetometry, we investigated anisotropic high-field (H less than or similar to 7T) low-temperature (10 K) magnetization response of inhomogeneous nanoisland FeNi films grown by rf sputtering deposition on Sitall (TiO2) glass substrates. In the grown FeNi films, the FeNi layer nominal thickness varied from 0.6 to 2.5 nm, across the percolation transition at the d(c) similar or equal to 1.8 nm. We discovered that, beyond conventional spin-magnetism of Fe21Ni79 permalloy, the extracted out-of-plane magnetization response of the nanoisland FeNi films is not saturated in the range of investigated magnetic fields and exhibits paramagnetic-like behavior. We found that the anomalous out-of-plane magnetization response exhibits an escalating slope with increase in the nominal film thickness from 0.6 to 1.1 nm, however, it decreases with further increase in the film thickness, and then practically vanishes on approaching the FeNi film percolation threshold. At the same time, the in-plane response demonstrates saturation behavior above 1.5-2T, competing with anomalously large diamagnetic-like response, which becomes pronounced at high magnetic fields. It is possible that the supported-metal interaction leads to the creation of a thin charge-transfer (CT) layer and a Schottky barrier at the FeNi film/Sitall (TiO2) interface. Then, in the system with nanoscale circular domains, the observed anomalous paramagnetic-like magnetization response can be associated with a large orbital moment of the localized electrons. In addition, the inhomogeneous nanoisland FeNi films can possess spontaneous ordering of toroidal moments, which can be either of orbital or spin origin. The system with toroidal inhomogeneity can lead to anomalously strong diamagnetic-like response. The observed magnetization response is determined by the interplay between the paramagnetic-and diamagnetic-like contributions.
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.