Editorial: Combining Simulations, Theory, and Experiments into Multiscale Models of Biological Events

10.3389/fmolb.2021.797754Frontiers in Molecular Biosciences879775

Molecular dynamics simulations and docking of non-nucleoside reverse transcriptase inhibitors (NNRTIs): a possible approach to personalized HIV treatment : from 7th German Conference on Chemoinformatics: 25 CIC-Workshop Goslar, Germany, 6 - 8 November 2011

The human immunodeficiency virus (HIV) is currently ranked sixth in the worldwide causes of death [1]. One treatment approach is to inhibit reverse transcriptase (RT), an enzyme essential for reverse transcription of viral RNA into DNA before integration into the host genome [2]. By using non-nucleoside RT inhibitors (NNRTIs) [3], which target an allosteric binding site, major side effects can be evaded. Unfortunately, high genetic variability of HIV in combination with selection pressure introduced by drug treatment enables the virus to develop resistance against this drug class by developing point mutations. This situation necessitates treatment with alternative NNRTIs that target the particular RT mutants encountered in a patient. Previously, proteochemometric approaches have demonstrated some success in predicting binding of particular NNRTIs to individual mutants; however a structurebased approach may help to further improve the predictive success of such models. Hence, our aim is to rationalize the experimental activity of known NNRTIs against a variety of RT mutants by combining molecular modeling, long-timescale atomistic molecular dynamics (MD) simulation sampling and ensemble docking. Initial control experiments on known inhibitor-RT mutant complexes using this protocol were successful, and the predictivity for further complexes is currently being evaluated. In addition to predictive power, MD simulations of multiple RT mutants are providing fundamental insight into the dynamics of the allosteric NNRTI binding site which is useful for the design of future inhibitors. Overall, work of this type is hoped to contribute to the development of predictive efficacy models for individual patients, and hence towards personalized HIV treatment options

Linked health data for pharmacovigilance in children : Perceived legal and ethical issues for stakeholders and data guardians

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Testing Gaussian random hypothesis with the cosmic microwave background temperature anisotropies in the three-year WMAP data

We test the hypothesis that the temperature of the cosmic microwave background is consistent with a Gaussian random field defined on the celestial sphere, using de-biased internal linear combination (DILC) map produced from the 3-year WMAP data. We test the phases for spherical harmonic modes with l <= 10 (which should be the cleanest) for their uniformity, randomness, and correlation with those of the foreground templates. The phases themselves are consistent with a uniform distribution, but not for l <= 5, and the differences between phases are not consistent with uniformity. For l=3 and l=6, the phases of the CMB maps cross-correlate with the foregrounds, suggestion the presence of residual contamination in the DLC map even on these large scales. We also use a one-dimensional Fourier representation to assemble a_lm into the \Delta T_l(\phi) for each l mode, and test the positions of the resulting maxima and minima for consistency with uniformity randomness on the unit circle. The results show significant departures at the 0.5% level, with the one-dimensional peaks being concentrated around \phi=180 degs. This strongly significant alignment with the Galactic meridian, together with the cross-correlation of DILC phases with the foreground maps, strongly suggests that even the lowest spherical harmonic modes in the map are significantly contaminated with foreground radiation.Comment: submitted to ApJL, one paragraph is added in Section 3 and some more in the Referenc

On the ion coupling mechanism of the MATE transporter ClbM

Bacteria use a number of mechanisms to defend themselves from antimicrobial drugs. One important defense strategy is the ability to export drugs by multidrug transporters. One class of multidrug transporter, the so-called multidrug and toxic compound extrusion (MATE) transporters, extrude a variety of antibiotic compounds from the bacterial cytoplasm. These MATE transporters are driven by a Na+, H+, or combined Na+/H+ gradient, and act as antiporters to drive a conformational change in the transporter from the outward to the inward-facing conformation. In the inward-facing conformation, a chemical compound (drug) binds to the protein, resulting in a switch to the opposite conformation, thereby extruding the drug. Using molecular dynamics simulations, we now report the structural basis for Na+ and H+ binding in the dual ion coupled MATE transporter ClbM from Escherichia coli, which is connected to colibactin-induced genotoxicity, yielding novel insights into the ion/drug translocation mechanism of this bacterial transporter.</p

Molecular dynamics simulations and docking of non-nucleoside reverse transcriptase inhibitors (NNRTIs): a possible approach to personalized HIV treatment

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Single mutations in the ε subunit from thermophilic Bacillus PS3 generate a high binding affinity site for ATP

The ε subunit from ATP synthases acts as an ATP sensor in the bacterial cell to prevent ATP hydrolysis and thus the waste of ATP under conditions of low ATP concentration. However, the ATP binding affinities from various bacterial organisms differ markedly, over several orders of magnitude. For example, the ATP synthases from thermophilic Bacillus PS3 and Escherichia coli exhibit affinities of 4 µM and 22 mM, respectively. The recently reported R103A/R115A double mutant of Bacillus PS3 ATP synthase demonstrated an increased binding affinity by two orders of magnitude with respect to the wild type. Here, we used atomic-resolution molecular dynamics simulations to determine the role of the R103A and R115A single mutations. These lead us to predict that both single mutations also cause an increased ATP binding affinity. Evolutionary analysis reveals R103 and R115 substitutions in the ε subunit from other bacillic organisms, leading us to predict they likely have a higher ATP binding affinity than previously expected

Determining Customary International Law Relative to the Conduct of Hostilities in Non-international Armed Conflicts

In 1987, the 6th annual American Red Cross-Washington College of Law Conference on International Humanitarian Law convened to discuss the 1977 Protocols Additional to the 1949 Geneva Conventions. This article outlines the proceedings of the various workshops, serving as a richly detailed scholarly source for a significant historical event

Dynamics of crowded vesicle: local and global responses to membrane composition

The bacterial cell envelope is composed of a mixture of different lipids and proteins, making it an inherently complex organelle. The interactions between integral membrane proteins and lipids are crucial for their respective spatial localization within bacterial cells. We have employed microsecond timescale coarse-grained molecular dynamics simulations of vesicles of varying sizes and with a range of protein and lipid compositions, and used novel approaches to measure both local and global system dynamics, the latter based on spherical harmonics analysis. Our results suggest that both hydrophobic mismatch, enhanced by embedded membrane proteins, and curvature based sorting, due to different modes of undulation, may drive assembly in vesicular systems. Interestingly, the modes of undulation of the vesicles were found to be altered by the specific protein and lipid composition of the vesicle. Strikingly, lipid dynamics were shown to be coupled to proteins up to 6 nm from their surface, a substantially larger distance than has previously been observed, resulting in multi-layered annular rings enriched with particular types of phospholipid. Such large protein-lipid complexes may provide a mechanism for long-range communication. Given the complexity of bacterial membranes, our results suggest that subtle changes in lipid composition may have major implications for lipid and protein sorting under a curvature-based membrane-sorting model