Search results for "molecular dynamics simulation"
showing 10 items of 260 documents
The effects of pressure on the energy landscape of proteins
2018
AbstractProtein dynamics is characterized by fluctuations among different conformational substates, i.e. the different minima of their energy landscape. At temperatures above ~200 K, these fluctuations lead to a steep increase in the thermal dependence of all dynamical properties, phenomenon known as Protein Dynamical Transition. In spite of the intense studies, little is known about the effects of pressure on these processes, investigated mostly near room temperature. We studied by neutron scattering the dynamics of myoglobin in a wide temperature and pressure range. Our results show that high pressure reduces protein motions, but does not affect the onset temperature for the Protein Dynam…
An Integrated Pharmacophore/Docking/3D-QSAR Approach to Screening a Large Library of Products in Search of Future Botulinum Neurotoxin A Inhibitors
2020
Botulinum toxins are neurotoxins produced by Clostridium botulinum. This toxin can be lethal for humans as a cause of botulism
Two differential binding mechanisms of FG-nucleoporins and nuclear transport receptors
2018
Summary Phenylalanine-glycine-rich nucleoporins (FG-Nups) are intrinsically disordered proteins, constituting the selective barrier of the nuclear pore complex (NPC). Previous studies showed that nuclear transport receptors (NTRs) were found to interact with FG-Nups by forming an “archetypal-fuzzy” complex through the rapid formation and breakage of interactions with many individual FG motifs. Here, we use single-molecule studies combined with atomistic simulations to show that, in sharp contrast, FG-Nup214 undergoes a coupled reconfiguration-binding mechanism when interacting with the export receptor CRM1. Association and dissociation rate constants are more than an order of magnitude lowe…
Identification of estrogen receptor α ligands with virtual screening techniques.
2016
Utilization of computer-aided molecular discovery methods in virtual screening (VS) is a cost-effective approach to identify novel bioactive small molecules. Unfortunately, no universal VS strategy can guarantee high hit rates for all biological targets, but each target requires distinct, fine-tuned solutions. Here, we have studied in retrospective manner the effectiveness and usefulness of common pharmacophore hypothesis, molecular docking and negative image-based screening as potential VS tools for a widely applied drug discovery target, estrogen receptor α (ERα). The comparison of the methods helps to demonstrate the differences in their ability to identify active molecules. For example,…
Kinetic evidence for interaction of TMPyP4 with two different G-quadruplex conformations of human telomeric DNA
2018
Background: Stabilization of G-quadruplex helices by small ligands has attracted growing attention because they inhibit the activity of the enzyme telomerase, which is overexpressed in> 80% cancer cells. TMPyP4, one of the most studied G-quadruplex ligands, is used as a model to show that the ligands can exhibit different binding features with different conformations of a human telomeric specific sequence. Methods: UV–Vis, FRET melting Assay, Isothermal Titration Calorimetry, Time-resolved Fluorescence lifetime, T-Jump and Molecular Dynamics. Results: TMPyP4 yields two different complexes with two Tel22 telomeric conformations in the presence of Na+ or K+. T-Jump kinetic experiments show th…
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…
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 …
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…