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

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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

Full-length OmpA: structure, function, and membrane interactions predicted by molecular dynamics simulations

OmpA is a multidomain protein found in the outer membranes of most Gram-negative bacteria. Despite a wealth of reported structural and biophysical studies, the structure-function relationships of this protein remain unclear. For example, it is still debated whether it functions as a pore, and the precise molecular role it plays in attachment to the peptidoglycan of the periplasm is unknown. The absence of a consensus view is partly due to the lack of a complete structure of the full-length protein. To address this issue, we performed molecular-dynamics simulations of the full-length model of the OmpA dimer proposed by Robinson and co-workers. The N-terminal domains were embedded in an asymmetric model of the outer membrane, with lipopolysaccharide molecules in the outer leaflet and phospholipids in the inner leaflet. Our results reveal a large dimerization interface within the membrane environment, ensuring that the dimer is stable over the course of the simulations. The linker is flexible, expanding and contracting to pull the globular C-terminal domain up toward the membrane or push it down toward the periplasm, suggesting a possible mechanism for providing mechanical stability to the cell. The external loops were more stabilized than was observed in previous studies due to the extensive dimerization interface and presence of lipopolysaccharide molecules in our outer-membrane model, which may have functional consequences in terms of OmpA adhesion to host cells. In addition, the pore-gating behavior of the protein was modulated compared with previous observations, suggesting a possible role for dimerization in channel regulation

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

Linker length affects photostability of protein-targeted sensor of cellular microviscosity.

Viscosity sensitive fluorophores termed 'molecular rotors' represent a convenient and quantitative tool for measuring intracellular viscosity via Fluorescence Lifetime Imaging Microscopy (FLIM). We compare the FLIM performance of two BODIPY-based molecular rotors bound to HaloTag protein expressed in different subcellular locations. While both rotors are able to penetrate live cells and specifically label the desired intracellular location, we found that the rotor with a longer HaloTag protein recognition motif was significantly affected by photo-induced damage when bound to the HaloTag protein, while the other dye showed no changes upon irradiation. Molecular dynamics modelling indicates that the irradiation-induced electron transfer between the BODIPY moiety and the HaloTag protein is a plausible explanation for these photostability issues. Our results demonstrate that binding to the targeted protein may significantly alter the photophysical behaviour of a fluorescent probe and therefore its thorough characterisation in the protein bound form is essential prior to any in vitro and in cellulo applications