Search results for " Dynamics"
showing 10 items of 4108 documents
Asymmetry Between Pre- and Postsynaptic Transient Nanodomains Shapes Neuronal Communication.
2020
Synaptic transmission and plasticity are shaped by the dynamic reorganization of signaling molecules within pre- and postsynaptic compartments. The nanoscale organization of key effector molecules has been revealed by single-particle trajectory (SPT) methods. Interestingly, this nanoscale organization is highly heterogeneous. For example, presynaptic voltage-gated calcium channels (VGCCs) and postsynaptic ligand-gated ion channels such as AMPA receptors (AMPARs) are organized into so-called nanodomains where individual molecules are only transiently trapped. These pre- and postsynaptic nanodomains are characterized by a high density of molecules but differ in their molecular organization an…
Exploring the readthrough of nonsense mutations by non-acidic Ataluren analogues selected by ligand-based virtual screening
2016
Abstract Ataluren, also known as PTC124, is a 5-(fluorophenyl)-1,2,4-oxadiazolyl-benzoic acid suggested to suppress nonsense mutations by readthrough of premature stop codons in the mRNA. Potential interaction of PTC124 with mRNA has been recently studied by molecular dynamics simulations highlighting the importance of H-bonding and stacking π−π interactions. A series of non-acidic analogues of PTC124 were selected from a large database via a ligand-based virtual screening approach. Eight of them were synthesized and tested for their readthrough activity using the Fluc reporter harboring the UGA premature stop codon. The most active compound was further tested for suppression of the UGA non…
Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL
2016
AbstractThe function of monoacylglycerol lipase (MGL), a key actor in the hydrolytic deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2AG), is tightly controlled by the cell’s redox state: oxidative signals such as hydrogen peroxide suppress MGL activity in a reversible manner through sulfenylation of the peroxidatic cysteines, C201 and C208. Here, using as a starting point the crystal structures of human MGL (hMGL), we present evidence from molecular dynamics and metadynamics simulations along with high-resolution mass spectrometry studies indicating that sulfenylation of C201 and C208 alters the conformational equilibrium of the membrane-associated lid domain of MGL to favo…
Wavelength selection of rippling patterns in myxobacteria
2016
Rippling patterns of myxobacteria appear in starving colonies before they aggregate to form fruiting bodies. These periodic traveling cell density waves arise from the coordination of individual cell reversals, resulting from an internal clock regulating them, and from contact signaling during bacterial collisions. Here we revisit a mathematical model of rippling in myxobacteria due to Igoshin et al.\ [Proc. Natl. Acad. Sci. USA {\bf 98}, 14913 (2001) and Phys. Rev. E {\bf 70}, 041911 (2004)]. Bacteria in this model are phase oscillators with an extra internal phase through which they are coupled to a mean-field of oppositely moving bacteria. Previously, patterns for this model were obtaine…
An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge
2018
Molecular dynamics (MD) has become increasingly popular due to the development of hardware and software solutions and the improvement in algorithms, which allowed researchers to scale up calculations in order to speed them up. MD simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile analysis over time. In recent years, the development of new tools able to deeply explore a potential energy surface (PES) has allowed researchers to focus on the dynamic nature of the binding recognition process and binding-induced protein conformational changes. Moreover, modern approaches have been demonstrated to be effective and reliable in …
Physical mechanisms of micro- and nanodomain formation in multicomponent lipid membranes.
2016
This article summarizes a variety of physical mechanisms proposed in the literature, which can generate micro- and nanodomains in multicomponent lipid bilayers and biomembranes. It mainly focusses on lipid-driven mechanisms that do not involve direct protein-protein interactions. Specifically, it considers (i) equilibrium mechanisms based on lipid-lipid phase separation such as critical cluster formation close to critical points, and multiple domain formation in curved geometries, (ii) equilibrium mechanisms that stabilize two-dimensional microemulsions, such as the effect of linactants and the effect of curvature-composition coupling in bilayers and monolayers, and (iii) non-equilibrium me…
Intramolecular structural parameters are key modulators of the gel-liquid transition in coarse grained simulations of DPPC and DOPC lipid bilayers
2018
The capability of coarse-grained models based on the MARTINI mapping to reproduce the gel-liquid phase transition in saturated and unsaturated model lipids was investigated. We found that the model is able to reproduce a lower critical temperature for 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) with respect to 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Nonetheless, the appearance of a gel phase for DOPC is strictly dependent on the intramolecular parameters chosen to model its molecular structure. In particular, we show that the bending angle at the coarse-grained bead corresponding to the unsaturated carbon-carbon bond acts as an order parameter determining the temperature of …
Stochastic sampling effects favor manual over digital contact tracing.
2020
Isolation of symptomatic individuals, tracing and testing of their nonsymptomatic contacts are fundamental strategies for mitigating the current COVID-19 pandemic. The breaking of contagion chains relies on two complementary strategies: manual reconstruction of contacts based on interviews and a digital (app-based) privacy-preserving contact tracing. We compare their effectiveness using model parameters tailored to describe SARS-CoV-2 diffusion within the activity-driven model, a general empirically validated framework for network dynamics. We show that, even for equal probability of tracing a contact, manual tracing robustly performs better than the digital protocol, also taking into accou…
Coarse-grained models of double-stranded DNA based on experimentally determined knotting probabilities
2018
Abstract To accurately model double-stranded DNA in a manner that is computationally efficient, coarse-grained models of DNA are introduced, where model parameters are selected by fitting the spectrum of observable DNA knots: We develop a general method to fit free parameters of coarse-grained chain models by comparing experimentally obtained knotting probabilities of short DNA chains to knotting probabilities that are computed in Monte Carlo simulations, resulting in coarse-grained DNA models which are tailored to reflect DNA topology in the best possible way. The method is exemplified by fitting ideal chain models as well as a bead-spring model with excluded volume interactions, to model …
KnotGenome: a server to analyze entanglements of chromosomes.
2018
Abstract The KnotGenome server enables the topological analysis of chromosome model data using three-dimensional coordinate files of chromosomes as input. In particular, it detects prime and composite knots in single chromosomes, and links between chromosomes. The knotting complexity of the chromosome is presented in the form of a matrix diagram that reveals the knot type of the entire polynucleotide chain and of each of its subchains. Links are determined by means of the Gaussian linking integral and the HOMFLY-PT polynomial. Entangled chromosomes are presented graphically in an intuitive way. It is also possible to relax structure with short molecular dynamics runs before the analysis. Kn…