Dimensionality reduction via coarse grain modeling is a valuable tool in biomolecular research. For large assemblies, ultra coarse models are often knowledge-based, relying on a priori information to ...parameterize models thus hindering general predictive capability. Here, we present substantial advances to the shape based coarse graining (SBCG) method, which we refer to as SBCG2. SBCG2 utilizes a revitalized formulation of the topology representing network which makes high-granularity modeling possible, preserving atomistic details that maintain assembly characteristics. Further, we present a method of granularity selection based on charge density Fourier Shell Correlation and have additionally developed a refinement method to optimize, adjust and validate high-granularity models. We demonstrate our approach with the conical HIV-1 capsid and heteromultimeric cofilin-2 bound actin filaments. Our approach is available in the Visual Molecular Dynamics (VMD) software suite, and employs a CHARMM-compatible Hamiltonian that enables high-performance simulation in the GPU-resident NAMD3 molecular dynamics engine.
The human endogenous retrovirus K (HERV-K) is the most recently acquired endogenous retrovirus in the human genome and is activated and expressed in many cancers and amyotrophic lateral sclerosis. We ...present the immature HERV-K capsid structure at 3.2 Å resolution determined from native virus-like particles using cryo-electron tomography and subtomogram averaging. The structure shows a hexamer unit oligomerized through a 6-helix bundle, which is stabilized by a small molecule analogous to IP6 in immature HIV-1 capsid. The HERV-K immature lattice is assembled via highly conserved dimer and trimer interfaces, as detailed through all-atom molecular dynamics simulations and supported by mutational studies. A large conformational change mediated by the linker between the N-terminal and the C-terminal domains of CA occurs during HERV-K maturation. Comparison between HERV-K and other retroviral immature capsid structures reveals a highly conserved mechanism for the assembly and maturation of retroviruses across genera and evolutionary time.
Hydrogen peroxide is the main metabolite effective in redox regulation and it is considered an insulinomimetic agent, with insulin signalling being essential for normal mitochondrial function in ...cardiomyocytes. Therefore, the aim of this work was to deeply analyse the heart mitochondrial H2O2 metabolism, in the early stage of type 1 diabetes. Diabetes was induced by Streptozotocin (STZ, single dose, 60 mg × kg−1, ip.) in male Wistar rats and the animals were sacrificed 10 days after injection. Mitochondrial membrane potential and ATP production, using malate-glutamate as substrates, in the heart of diabetic animals were like the ones observed in control group. Mn-SOD activity was lower (15%) in the heart of diabetic rats even though its expression was increased (29%). The increment in heart mitochondrial H2O2 production (117%) in diabetic animals was accompanied by an enhancement in the activities and expressions of glutathione peroxidase (26% and 42%) and of catalase (200% and 133%), with no changes in the peroxiredoxin activity, leading to H2O2ss ∼40 nM. Heart mitochondrial lipid peroxidation and protein nitration were higher in STZ-injected animals (45% and 42%) than in control group. The mitochondrial membrane potential and ATP production preservation suggest the absence of irreversible damage at this early stage of diabetes 1. The increase in mitochondrial H2O2ss above the physiological range, but still below supraphysiological concentration (∼100 nM) seems to be part of the adaptive response triggered in cardiomyocytes due to the absence of insulin. The signs of mitochondrial dysfunction observed in this very early stage of diabetes are consistent with the mitochondrial entity called ″complex I syndrome″.
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•Cardiac mitochondria exhibit “complex I syndrome” after 7 days of hyperglycemia.•An adaptive response is triggered in heart mitochondria due to lack of insulin.•Regulation of heart mitochondrial H2O2 metabolism is a central event in early DM 1.•H2O2ss in the heart mitochondrial matrix is controlled by GPx and Prx systems.•Heart mitochondrial ΔΨ and ATP generation are preserved 10 days post-STZ injection.
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an emerging class of small molecules that disrupt viral maturation by inducing the aberrant multimerization of IN. Here, we present cocrystal ...structures of HIV-1 IN with two potent ALLINIs, namely, BI-D and the drug candidate Pirmitegravir. The structures reveal atomistic details of the ALLINI-induced interface between the HIV-1 IN catalytic core and carboxyl-terminal domains (CCD and CTD). Projecting from their principal binding pocket on the IN CCD dimer, the compounds act as molecular glue by engaging a triad of invariant HIV-1 IN CTD residues, namely, Tyr226, Trp235, and Lys266, to nucleate the CTD-CCD interaction. The drug-induced interface involves the CTD SH3-like fold and extends to the beginning of the IN carboxyl-terminal tail region. We show that mutations of HIV-1 IN CTD residues that participate in the interface with the CCD greatly reduce the IN-aggregation properties of Pirmitegravir. Our results explain the mechanism of the ALLINI-induced condensation of HIV-1 IN and provide a reliable template for the rational development of this series of antiretrovirals through the optimization of their key contacts with the viral target.
Despite the remarkable success of combination antiretroviral therapy, HIV-1 remains among the major causes of human suffering and loss of life in poor and developing nations. To prevail in this drawn-out battle with the pandemic, it is essential to continue developing advanced antiviral agents to fight drug resistant HIV-1 variants. Allosteric integrase inhibitors (ALLINIs) are an emerging class of HIV-1 antagonists that are orthogonal to the current antiretroviral drugs. These small molecules act as highly specific molecular glue, which triggers the aggregation of HIV-1 integrase. In this work, we present high-resolution crystal structures that reveal the crucial interactions made by two potent ALLINIs, namely, BI-D and Pirmitegravir, with HIV-1 integrase. Our results explain the mechanism of drug action and will inform the development of this promising class of small molecules for future use in antiretroviral regimens.
Part of the abandoned cropland in Mediterranean landscapes is being subjected to afforestation dominated by pines. Here we simultaneously evaluate the effect of three categories of factors as ...predictors of the interspecific variation in bird habitat occupancy of fragmented afforestations, namely regional distribution, habitat preferences, and life-history traits of species. We use the “natural experiment” that highly fragmented pine plantations of central Spain represent due to the prevailing pattern of land ownership of small properties. Many species with marked habitat preferences for woodland habitats were very scarce or were never recorded in this novel habitat within a matrix of deforested agricultural landscape. Interspecific variability in occurrence was mainly explained by regional distribution patterns: occurrence was significantly and positively associated with the proportion of occupied 10 × 10 UTM km squares around the study area, habitat breadth, and population trend of species in the period 1998–2011. It was also positively associated with regional occupancy of mature and large pine plantations. Other predictor variables related to habitat preferences (for woodland, agricultural and urban habitats) or life-history traits (migratory strategy, body mass, and clutch size) were unrelated to the occurrence of species. Thus, small man-made pinewood islands funded by the Common Agrarian Policy within a landscape dominated by Mediterranean agricultural habitats only capture widespread and habitat generalist avian species with increasing population trends, not contributing to enhance truly woodland species.
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•Efficient classifier capable of overcoming inherent problems of small-data training sets.•Automated detection and classification of HIV-1 particle morphology from transmission ...electron micrographs.•Three orders of magnitude speed increase in data processing with negligible loss in accuracy.
Transmission electron microscopy (TEM) has a multitude of uses in biomedical imaging due to its ability to discern ultrastructure morphology at the nanometer scale. Through its ability to directly visualize virus particles, TEM has for several decades been an invaluable tool in the virologist’s toolbox. As applied to HIV-1 research, TEM is critical to evaluate activities of inhibitors that block the maturation and morphogenesis steps of the virus lifecycle. However, both the preparation and analysis of TEM micrographs requires time consuming manual labor. Through the dedicated use of computer vision frameworks and machine learning techniques, we have developed a convolutional neural network backbone of a two-stage Region Based Convolutional Neural Network (RCNN) capable of identifying, segmenting and classifying HIV-1 virions at different stages of maturation and morphogenesis. Our results outperformed common RCNN backbones, achieving 80.0% mean Average Precision on a diverse set of micrographs comprising different experimental samples and magnifications. We expect that this tool will be of interest to a broad range of researchers.
Afforestation programs such as the one promoted by the EU Common Agricultural Policy have spread tree plantations on former cropland. These afforestations attract generalist forest and ubiquitous ...species but may cause severe damage to open habitat species, especially birds of high conservation value. We investigated the effects of young (<20 yr) tree plantations dominated by pine P. halepensis on bird communities inhabiting the adjacent open farmland habitat in central Spain. We hypothesize that pine plantations located at shorter distances from open fields and with larger surface would affect species richness and conservation value of bird communities. Regression models controlling for the influence of land use types around plantations revealed positive effects of higher distance to pine plantation edge on community species richness in winter, and negative effects on an index of conservation concern (SPEC) during the breeding season. However, plantation area did not have any effect on species richness or community conservation value. Our results indicate that the effects of pine afforestation on bird communities inhabiting Mediterranean cropland are diluted by heterogeneous agricultural landscapes.
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