The interaction with gold suppresses fiber-like conformations of the amyloid beta (16-22) peptide

Inorganic surfaces and nanoparticles can accelerate or inhibit the fibrillation process of proteins and peptides, including the biomedically relevant amyloid β peptide. However, the microscopic mechanisms that determine such an effect are still poorly understood. By means of large-scale, state-of-the-art enhanced sampling molecular dynamics simulations, here we identify an interaction mechanism between the segments 16–22 of the amyloid β peptide, known to be fibrillogenic by itself, and the Au(111) surface in water that leads to the suppression of fiber-like conformations from the peptide conformational ensemble. Moreover, thanks to advanced simulation analysis techniques, we characterize the conformational selection vs. induced fit nature of the gold effect. Our results disclose an inhibition mechanism that is rooted in the details of the microscopic peptide–surface interaction rather than in general phenomena such as peptide sequestration from the solution.ISSN:2040-3364ISSN:2040-337

General, PDB-based collective variables for protein folding

New, automated forms of data analysis are required to understand the high-dimensional trajectories that are obtained from molecular dynamics simulations on proteins. Dimensionality reduction algorithms are particularly appealing in this regard as they allow one to construct unbiased, low-dimensional representations of the trajectory using only the information encoded in the trajectory. The downside of this approach is that a different set of coordinates are required for each different chemical system under study precisely because the coordinates are constructed using information from the trajectory. In this paper, we show how one can resolve this problem by using the sketch-map algorithm that we recently proposed to construct a low-dimensional representation of the structures contained in the protein data bank. We show that the resulting coordinates are as useful for analyzing trajectory data as coordinates constructed using landmark configurations taken from the trajectory and that these coordinates can thus be used for understanding protein folding across a range of systems

Retinal isomerization and water-pore formation in channelrhodopsin-2

Channelrhodopsin-2 (ChR2) is a light-sensitive ion channel widely used in optogenetics. Photoactivation triggers a trans-to-cis isomerization of a covalently bound retinal. Ensuing conformational changes open a cation-selective channel. We explore the structural dynamics in the early photocycle leading to channel opening by classical (MM) and quantum mechanical (QM) molecular simulations. With QM/MM simulations, we generated a protein-adapted force field for the retinal chromophore, which we validated against absorption spectra. In a 4-µs MM simulation of a dark-adapted ChR2 dimer, water entered the vestibules of the closed channel. Retinal all-trans to 13-cis isomerization, simulated with metadynamics, triggered a major restructuring of the charge cluster forming the channel gate. On a microsecond time scale, water penetrated the gate to form a membrane-spanning preopen pore between helices H1, H2, H3, and H7. This influx of water into an ion-impermeable preopen pore is consistent with time-resolved infrared spectroscopy and electrophysiology experiments. In the retinal 13-cis state, D253 emerged as the proton acceptor of the Schiff base. Upon proton transfer from the Schiff base to D253, modeled by QM/MM simulations, we obtained an early-M/P2 390-like intermediate. Rapid rotation of the unprotonated Schiff base toward the cytosolic side effectively prevents its reprotonation from the extracellular side. From MM and QM simulations, we gained detailed insight into the mechanism of ChR2 photoactivation and early events in pore formation. By rearranging the network of charges and hydrogen bonds forming the gate, water emerges as a key player in light-driven ChR2 channel opening

Improved leakage-equilibration-absorption scheme ( ileas ) for neutrino physics in compact object mergers

We present a new, computationally efficient, energy-integrated approximation for neutrino effects in hot and dense astrophysical environments such as supernova cores and compact binary mergers and their remnants. Our new method, termed ILEAS for Improved Leakage-Equilibration-Absorption Scheme, improves the lepton-number and energy losses of traditional leakage descriptions by a novel prescription of the diffusion time-scale based on a detailed energy integral of the flux-limited diffusion equation. The leakage module is supplemented by a neutrino-equilibration treatment that ensures the proper evolution of the total lepton number and medium plus neutrino energies as well as neutrino-pressure effects in the neutrino-trapping domain. Moreover, we employ a simple and straightforwardly applicable ray-tracing algorithm for including re-absorption of escaping neutrinos especially in the decoupling layer and during the transition to semi-transparent conditions. ILEAS is implemented on a three-dimensional (3D) Cartesian grid with a minimum of free and potentially case-dependent parameters and exploits the basic physics constraints that should be fulfilled in the neutrino-opaque and free-streaming limits. We discuss a suite of tests for stationary and time-dependent proto-neutron star models and post-merger black-hole-torus configurations, for which 3D ILEAS results are demonstrated to agree with energy-dependent 1D and 2D two-moment (M1) neutrino transport on the level of 10--15 percent in basic neutrino properties. This also holds for the radial profiles of the neutrino luminosities and of the electron fraction. Even neutrino absorption maps around torus-like neutrino sources are qualitatively similar without any fine-tuning, confirming that ILEAS can satisfactorily reproduce local losses and re-absorption of neutrinos as found in sophisticated transport calculations.Comment: 39 pages, 19 figures; revised version incl. referee requests; new Sect.3.4 with first NS-NS merger models added; accepted by MNRA

The conformational free energy landscape of beta-D-glucopyranose. implications for substrate preactivation in beta-glucoside hydrolases

Using ab initio metadynamics we have computed the conformational free energy landscape of beta-D-glucopyranose as a function of the puckering coordinates. We show that the correspondence between the free energy and the Stoddard's pseudorotational itinerary for the system is rather poor. The number of free energy minima (9) is smaller than the number of ideal structures (13). Moreover, only six minima correspond to a canonical conformation. The structural features, the electronic properties, and the relative stability of the predicted conformers permit the rationalization of the occurrence of distorted sugar conformations in all the available X-ray structures of beta-glucoside hydrolase Michaelis complexes. We show that these enzymes recognize the most stable distorted conformers of the isolated substrate and at the same time the ones better prepared for catalysis in terms of bond elongation/shrinking and charge distribution. This suggests that the factors governing the distortions present in these complexes are largely dictated by the intrinsic properties of a single glucose unit

Activity and diversity of haloalkaliphilic methanogens in Central Asian soda lakes

Methanogens are of biotechnological interest because of their importance in biogas production. Here we investigate the suitability of sediments from Central Asian soda lakes as inoculum for high pH methane-producing bioreactors. Methane production in these sediments was modest (up to 2.5 μmol mL sediment), with methanol and hydrogen as the preferred substrates. The responsible methanogenic community was characterized based on mcrA gene sequences. McrA gene sequences so far specific to these habitats indicated the presence of two clusters within the orders Methanobacteriales and Methanomicrobiales, one apparently including representatives of the genus Methanocalculus and another distantly related to the genus Methanobacterium

Inhibition of DPP-IV Activity and Stimulation of GLP-1 Release by Gastrointestinally Digested Black Soldier Fly Prepupae

The beneficial effects of an insect-based diet on human health and, in particular, the regulatory ability of digested insects’ proteins on the glycaemic response in humans are topics that need to be investigated deeper. In this work, we performed an in vitro study on the modulatory activity of gastrointestinal digested black soldier fly (BSF) prepupae on the enterohormone GLP-1 and its natural inhibitor, DPP-IV. We verified whether actions intended to valorise the starting insect biomass, i.e., insect-optimised growth substrates and prior fermentation, can positively impact human health. Our results highlight that the digested BSF proteins from all the prepupae samples had a high stimulatory and inhibitory ability on the GLP-1 secretion and the DPP-IV enzyme in the human GLUTag cell line. Gastrointestinal digestion significantly improved the DPP-IV inhibitory capacity of the whole insect protein. Moreover, it was seen that optimised diets or fermentation processes preceding the digestion, in any case, did not positively affect the efficacy of the answer. BSF was already considered one of the edible insects more suitable for human consumption for its optimal nutritional profile. The BSF bioactivity here shown, after simulated digestion, on glycaemic control systems makes this species even more promising

Dietary fatty acid composition is sensed by the NLRP3 inflammasome: omega-3 fatty acid (DHA) prevents NLRP3 activation in human macrophages

The Nod-like receptor protein 3 (NLRP3) inflammasome is considered to be a pivotal host platform responsible for sensing of exogenous and endogenous danger signals, including those generated as a result of metabolic dysregulation, and for the subsequent, IL-1β-mediated orchestration of inflammatory and innate immunity responses. In this way, although the molecular link between diet-induced obesity and inflammasome activation is still unclear, free fatty acids (FFA) have been proposed as a triggering event. We report that dietary fatty acid (FA) composition is sensed by the NLRP3 inflammasome in human macrophages. For this purpose, we have analysed three roles of FA supplementation: as a priming signal for ATP-activated macrophages, in determining where the administration of dietary FAs interferes with LPS-mediated inflammasome activation and by inducing inflammasome activation per se. In this study, we confirm that saturated (SFAs) activated the NLRP3 inflammasome and stimulated the secretion of the IL-1β cytokine, while PUFAs were mainly inhibitors. Moreover, in general, DHA (n-3 PUFA) was more effective in preventing inflammasome activation than arachidonic acid (n-6 PUFA)