Search results for "Simulation."
showing 10 items of 4779 documents
De novo design of protein kinase inhibitors by in silico identification of hinge region-binding fragments.
2013
Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically feasible and can be elaborated to small molecule libraries. Starting from commercially available compounds, core fragments were extracted, filtered for pharmacophoric properties compatible w…
Full and Partial Agonism of Ionotropic Glutamate Receptors Indicated by Molecular Dynamics Simulations
2011
Ionotropic glutamate receptors (iGluRs) are synaptic proteins that facilitate signal transmission in the central nervous system. Extracellular iGluR cleft closure is linked to receptor activation; however, the mechanism underlying partial agonism is not entirely understood. Full agonists close the bilobed ligand-binding domain (LBD), while antagonists prevent closure; the transmembrane ion channel either opens or stays closed, respectively. Although some bulky partial agonists produce intermediate iGluR-LBD closure, the available crystal structures also imply that the cleft can be shut with certain partial agonists. Recently, we have shown that the iGluR-LBD closure stage can be recreated b…
Zinc Binding Sites Conserved in Short Neuropeptides Containing a Diphenylalanine Motif
2019
A diphenylalanine motif in peptides plays a crucial role in supramolecular systems. The current work represents a novel strategy in which a diphenylalanine motif in the central domain of neuropeptides conserves the specific Zn2+ binding site and prevents "hopping" of the Zn2+ ion between alternative metal binding sites. Alternative metal binding sites may also include carboxylic atoms in the terminal domains of a peptide. Therefore, one needs to design a peptide in which the metal will not bind the carboxylic groups in the terminal domains. Herein, we propose that engineering and designing peptides with a diphenylalanine motif in the central domain may yield excellent metal chelators.
The coffee-house: Upcycling spent coffee grounds for the production of green geopolymeric architectural energy-saving products
2023
This study investigates a possible alternative reuse of spent coffee grounds (SCG), the major residue of the brewing process, to manufacture green geopolymeric materials for innovative building applications in energy-saving construction, in line with the European Green Deal towards zero-energy building. Specimens were prepared by a combination of biomass fly ash from the Kraft paper-pulp process, as raw material (70 wt%), and SCG (up to 17.5 %), as filler. The high amount of reused bio-wastes makes the material fit the requirements for the Minimum Environmental Criteria (MEC) certification, in light of the Circular Economy (CE) approach. Sustainability is also boosted by the manufacturing p…
Molecular Dynamics Simulations of the Initial Adsorption Stages of Fibrinogen on Mica and Graphite Surfaces.
2015
Fibrinogen, a blood glycoprotein of vertebrates, plays an essential role in blood clotting by polymerizing into fibrin when activated. Upon adsorption on material surfaces, it also contributes to determine their biocompatibility and has been implicated in the onset of thrombosis and inflammation at medical implants. Here we present the first fully atomistic simulations of the initial stages of the adsorption process of fibrinogen on mica and graphite surfaces. The simulations reveal a weak adsorption on mica that allows frequent desorption and reorientation events. This adsorption is driven by electrostatic interactions between the protein and the silicate surface as well as the counterion …
Ultrafast myoglobin structural dynamics observed with an X-ray free-electron laser.
2014
Light absorption can trigger biologically relevant protein conformational changes. The light-induced structural rearrangement at the level of a photoexcited chromophore is known to occur in the femtosecond timescale and is expected to propagate through the protein as a quake-like intramolecular motion. Here we report direct experimental evidence of such ‘proteinquake’ observed in myoglobin through femtosecond X-ray solution scattering measurements performed at the Linac Coherent Light Source X-ray free-electron laser. An ultrafast increase of myoglobin radius of gyration occurs within 1 picosecond and is followed by a delayed protein expansion. As the system approaches equilibrium it underg…
Solving gap metabolites and blocked reactions in genome-scale models: application to the metabolic network of Blattabacterium cuenoti
2013
Abstract Background Metabolic reconstruction is the computational-based process that aims to elucidate the network of metabolites interconnected through reactions catalyzed by activities assigned to one or more genes. Reconstructed models may contain inconsistencies that appear as gap metabolites and blocked reactions. Although automatic methods for solving this problem have been previously developed, there are many situations where manual curation is still needed. Results We introduce a general definition of gap metabolite that allows its detection in a straightforward manner. Moreover, a method for the detection of Unconnected Modules, defined as isolated sets of blocked reactions connect…
Enchytraeid population dynamics: Resource limitation and size-dependent mortality
2009
Abstract Enchytraeids are regarded as keystone soil organisms in forest ecosystems. Their abundance and biomass fluctuate widely. Predicting the consequences of anthropogenic disturbances requires an understanding of the mechanisms underlying enchytraeid population dynamics. Here I develop a simple model, which predicts that the type of dynamics is controlled by resource input rate. If fungal resource input is a discrete event once a year, an exponential growth phase is followed by starvation and sharp decline of enchytraeid abundance. Model simulations with three different forcing functions were compared to field data. Initial parameter values were obtained from various independent sources…
Assessment of Granger causality by nonlinear model identification: application to short-term cardiovascular variability.
2007
A method for assessing Granger causal relationships in bivariate time series, based on nonlinear autoregressive (NAR) and nonlinear autoregressive exogenous (NARX) models is presented. The method evaluates bilateral interactions between two time series by quantifying the predictability improvement (PI) of the output time series when the dynamics associated with the input time series are included, i.e., moving from NAR to NARX prediction. The NARX model identification was performed by the optimal parameter search (OPS) algorithm, and its results were compared to the least-squares method to determine the most appropriate method to be used for experimental data. The statistical significance of…
Mutual nonlinear prediction of cardiovascular variability series: Comparison between exogenous and autoregressive exogenous models
2007
A model-based approach to perform mutual nonlinear prediction of short cardiovascular variability series is presented. The approach is based on identifying exogenous (X) and autoregressive exogenous (ARX) models by K-nearest neighbors local linear approximation, and estimates the predictability of a series given the other as the squared correlation between original and predicted values of the series. The method was first tested on simulations reproducing different types of interaction between non-identical Henon maps, and then applied to heart rate (HR) and blood pressure (BP) variability series measured in healthy subjects at rest and after head-up tilt. Simulations showed that different c…