137 research outputs found
Identifying Ligand Binding Conformations of the β2-Adrenergic Receptor by Using Its Agonists as Computational Probes
No full textRecently available G-protein coupled receptor (GPCR) structures and biophysical studies suggest that the difference between the effects of various agonists and antagonists cannot be explained by single structures alone, but rather that the conformational ensembles of the proteins need to be considered. Here we use an elastic network model-guided molecular dynamics simulation protocol to generate an ensemble of conformers of a prototypical GPCR, β2-adrenergic receptor (β2AR). The resulting conformers are clustered into groups based on the conformations of the ligand binding site, and distinct conformers from each group are assessed for their binding to known agonists of β2AR. We show that the select ligands bind preferentially to different predicted conformers of β2AR, and identify a role of β2AR extracellular region as an allosteric binding site for larger drugs such as salmeterol. Thus, drugs and ligands can be used as "computational probes" to systematically identify protein conformers with likely biological significance. © 2012 Isin et al
THE ACTIVATION MECHANISM OF RHODOPSIN EXPLORED BY MULTISCALE METHODS
No full textRhodopsin is the best characterized member of the large, pharmaceutically important, family of G-protein-coupled receptors (GPCRs), and serves as a prototype for understanding GPCR activation. In this thesis, we aim at understanding the activation mechanism of rhodopsin. To this aim, we first performed an in-depth analysis of the conformational motions of rhodopsin predicted by two elastic network models, Gaussian Network Model (GNM) and Anisotropic Network Model (ANM). We compared these motions with the extensive amount of experimental data, and developed a model for rhodopsin activation. We tested the model with Meta II fluorescence decay rates measured to characterize the deactivation of rhodopsin mutants. We find that our results correctly predict 93% of the experimentally observed effects in 119 rhodopsin mutants for which the decay rates and misfolding data were measured, including a systematic analysis of Cys->Ser replacements. Next, in order to incorporate atomic details and the effects of membrane and water molecules into our model, we developed a new protocol named ANM-restrained molecular dynamics (MD). In this protocol, we used multiple ANM modes as restraints to guide MD simulations. By using this protocol, we were able to sample biologically relevant, large scale motions of the protein that are otherwise not accessible to the conventional timescales MD simulations. Furthermore, we explored the evolution of the multiple ANM global modes with realistic deformations favored by a detailed atomic force field in the presence of the explicit environment. Remarkably, with this method, we identify a highly hinge site, which does not change with several rounds of applying normal modes as restraints. This hinge site includes residues that are directly affected by the isomerization of retinal, as well as those stabilizing the resulting all-trans conformation of the chromophore. The CP ends of the helices H3, H4, H5, and H6 and the connecting loops are found to enjoy an enhanced mobility facilitated by this hinge site. Several new interactions are observed to contribute to the mechanism of signal propagation from the retinal binding pocket to the G-protein binding sites in the CP domain
A multiphase phase-field study of three-dimensional martensitic twinned microstructures at large strains
No full textA thermodynamically consistent multiphase phase-field approach for stress and temperature-induced martensitic phase transformation at the nanoscale and under large strains is developed. A total of N independent order parameters are considered for materials with N variants, where one of the order parameters describes A M transformations and the remaining N-1 independent order parameters describe the transformations between the variants. A non-contradictory gradient energy is used within the free energy of the system to account for the energies of the interfaces. In addition, a non-contradictory kinetic relationships for the rate of the order parameters versus thermodynamic driving forces is suggested. As a result, a system of consistent coupled Ginzburg-Landau equations for the order parameters are derived. The crystallographic solution for twins within twins is presented for the cubic to tetragonal transformations. A 3D complex twins within twins microstructure is simulated using the developed phase-field approach and a large-strain-based nonlinear finite element method. A comparative study between the crystallographic solution and the simulation result is presented.This is a pre-print of the article Basak, Anup, and Valery I. Levitas. "A multiphase phase-field study of three-dimensional martensitic twinned microstructures at large strains." arXiv preprint arXiv:2206.12576 (2022).
DOI: 10.48550/arXiv.2206.12576.
Copyright 2022 The Author(s).
Attribution 4.0 International (CC BY 4.0).
Posted with permission
Failure mechanisms in lithium silicon batteries
No full textLithium silicon (Li-Si) batteries offer more than ten times the theoretical specific capacity compared to current lithium ion battery technologies, by using a silicon anode. In practice however, the cycle life of Li-Si batteries is very limited. The large volume change of the silicon anode is known to be the main reason for this. Research on the volume changes during varying cell cycles and voltages is presented in this thesis and an experimental set up for a quasi in situ study of the SEI layer is suggested. Cycling tests with an amorphous silicon thin film of 220 nm deposited using magnetron sputtering on a copper foil current collector confirmed that the major cause of capacity loss is swelling of the silicon during lithiation, causing the silicon to detach from the current collector and resulting in significant capacity loss. Increasing the lower cut off voltage from 0 V to 0.2 V resulted in a slight improvement of cycle life. Silicon detachment also decreased as determined by SEM images. EFTEM and EDX mapping showed a clear split between a partially lithiated silicon layer on the surface and a pure silicon layer on the current collector side. It can be concluded that discharging Li-Si batteries to 0.2 V instead of 0 V is a promising method to reduce the swelling of silicon during lithiation.HREMQuantum NanoscienceApplied Science
Functional Motions of Influenza Virus Hemagglutinin: A Structure-Based Analytical Approach
No full textAbstractInfluenza virus hemagglutinin (HA), a homotrimeric integral membrane glycoprotein essential for viral infection, is engaged in two biological functions: recognition of target cells’ receptor proteins and fusion of viral and endosomal membranes, both requiring substantial conformational flexibility from the part of the glycoprotein. The different modes of collective motions underlying the functional mobility/adaptability of the protein are determined in the present study using an extension of the Gaussian network model (GNM) to treat concerted anisotropic motions. We determine the molecular mechanisms that may underlie HA function, along with the structural regions or residues whose mutations are expected to impede function. Good agreement between theoretically predicted fluctuations of individual residues and corresponding x-ray crystallographic temperature factors is found, which lends support to the GNM elucidation of the conformational dynamics of HA by focusing upon a subset of dominant modes. The lowest frequency mode indicates a global torsion of the HA trimer about its longitudinal axis, accompanied by a substantial mobility at the viral membrane connection. This mode is proposed to constitute the dominant molecular mechanism for the translocation and aggregation of HAs, and for the opening and dilation of the fusion pore. The second and third collective modes indicate a global bending, allowing for a large lateral surface exposure, which is likely to facilitate the close association of the viral and endosomal membranes before pore opening. The analysis of kinetically hot residues, in contrast, reveals a localization of energy centered around the HA2 residue Asp112, which apparently triggers the solvent exposure of the fusion peptide
Making Better Batteries: Following Electrochemistry at the Nano Scale with Electron Microscopy
No full textWith the focus in automobile industry to switch from petroleum-based vehicles to all electric vehicles, the increasing demand on harvesting energy from renewable sources for a safer and greener future and the ever-increasing demand of the portable electronics systems, the need for better batteries is eminent. The ultimate aim of battery research is to develop a low cost, light and small battery that can deliver high-capacity and/or high power. Lithium and sodium batteries are the frontrunners in achieving this ultimate battery. A macro battery is composed of thousands of millions of nanoparticles. Thus, to prepare a better battery we must determine the respective effects of electrode nanoparticle size, shape, structure, grain–grain boundary, defects and doping on the battery performance. To do so electrode nanoparticles need to be probed at the nano-scale to find out the correlation between their morphology, structure and chemical properties and their evolution due to the battery charging-discharging with battery performance. In this thesis we have utilized the unique capability of electron microscope to resolve the microstructural and chemical information at the (sub)nanometer scale to probe the electrode nanoparticles for making better batteries
Reflections on methodology for assessing campus sustainability from a Turkish perspective
No full textAim: The author provides a critical reflection of the questionnaire discussed at the workshop “Methodology for assessing the campus sustainability from the perspective of multi-level antifragility” held on Friday 13 May at the WSB University in Wrocław. The author reflects from the background of his experience in Turkey. Design / Research methods: The author provides his own reflections and opinions, based on the discussions at the workshop. Conclusions / findings: It is very difficult to create a set of indicators making campus sustainability internationally comparable, as well as finding proper sources of information. A starting point in creating such indicators may be mistakes threatening organizational viability and external sustainability Originality / value of the article: The article provides critical feedback on an innovative approach towards research on campus sustainability. </jats:p
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