Search results for "molecular dynamics simulation"
showing 10 items of 260 documents
Non-syndromic Mitral Valve Dysplasia Mutation Changes the Force Resilience and Interaction of Human Filamin A
2018
International audience; Filamin A (FLNa), expressed in endocardial endothelia during fetal valve morphogenesis, is key in cardiac development. Missense mutations in FLNa cause non-syndromic mitral valve dysplasia (FLNA-MVD). Here, we aimed to reveal the currently unknown underlying molecular mechanism behind FLNA-MVD caused by the FLNa P637Q mutation. The solved crystal structure of the FLNa3-5 P637Q revealed that this mutation causes only minor structural changes close to mutation site. These changes were observed to significantly affect FLNa's ability to transmit cellular force and to interact with its binding partner. The performed steered molecular dynamics simulations showed that signi…
How Fragile We Are: Influence of Stimulator of Interferon Genes (STING) Variants on Pathogen Recognition and Immune Response Efficiency.
2022
AbstractThe STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is o…
Histopathology of Skeletal Muscle in a Distal Motor Neuropathy Associated with a Mutant CCT5 Subunit: Clues for Future Developments to Improve Differ…
2023
Genetic chaperonopathies are rare but, because of misdiagnosis, there are probably more cases than those that are recorded in the literature and databases. This occurs because practitioners are generally unaware of the existence and/or the symptoms and signs of chaperonopathies. It is necessary to educate the medical community about these diseases and, with research, to unveil their mechanisms. The structure and functions of various chaperones in vitro have been studied, but information on the impact of mutant chaperones in humans, in vivo, is scarce. Here, we present a succinct review of the most salient abnormalities of skeletal muscle, based on our earlier report of a patient who carried…
CO rebinding kinetics and molecular dynamics simulations highlight dynamic regulation of internal cavities in human cytoglobin
2013
Abstract: Cytoglobin (Cygb) was recently discovered in the human genome and localized in different tissues. It was suggested to play tissue-specific protective roles, spanning from scavenging of reactive oxygen species in neurons to supplying oxygen to enzymes in fibroblasts. To shed light on the functioning of such versatile machinery, we have studied the processes supporting transport of gaseous heme ligands in Cygb. Carbon monoxide rebinding shows a complex kinetic pattern with several distinct reaction intermediates, reflecting rebinding from temporary docking sites, second order recombination, and formation (and dissociation) of a bis-histidyl heme hexacoordinated reaction intermediate…
The inhibition of glycerol permeation through aquaglyceroporin-3 induced by mercury(II)
2016
Mercurial compounds are known to inhibit water permeation through aquaporins (AQPs). Although in the last years some hypotheses were proposed, the exact mechanism of inhibition is still an open question and even less is known about the inhibition of the glycerol permeation through aquaglyceroporins. Molecular dynamics (MD) simulations of human aquaporin-3 (AQP3) have been performed up to 200 ns in the presence of Hg2+ ions. For the first time, we have observed the unbiased passage of a glycerol molecule from the extracellular to cytosolic side. Moreover, the presence of Hg2+ ions covalently bound to Cys40 leads to a collapse of the aromatic/arginine selectivity filter (ar/R SF), blocking th…
Design, Synthesis and Biological Evaluation of 7-Chloro-9
2019
Glycogen synthase kinase-3β (GSK-3β) represents a relevant drug target for the treatment of neurodegenerative pathologies including Alzheimer’s disease. We herein report on the optimization of a novel class of GSK-3β inhibitors based on the tofacitinib-derived screen hit 3-((3R,4R)-3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (1). We synthesized a series of 19 novel 7-chloro-9H-pyrimido[4,5-b]indole-based derivatives and studied their structure–activity relationships with focus on the cyanoacetyl piperidine moiety. We unveiled the crucial role of the nitrile group and its importance for the activity of this compound series. A successfu…
Adsorption of the herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA) by goethite.
2014
Interaction between the goethite surface and 4-chloro-2-methylphenoxyacetic acid (MCPA) herbicide was studied using density functional theory (DFT) calculations combined with molecular dynamics (MD). The important step made here lies in the use of a periodic DFT method enabling the study of a mineral surface of different protonation states, in strong contrast with previous molecular modeling studies limited to single protonation state corresponding to the point of zero charge. Different surface OH groups and MCPA proton states were used to mimic the strong effects of pH on the outer- and inner-sphere surface complexes that are theoretically possible, together with their binding energies, an…
Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings…
2016
The π-stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme-ligand binding studies complemented by high-level quantum chemical calculations. In the experimental study, the phenyl substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by additional interactions of the introduced fluo…
Comparative analysis of two paradigm bacteriophytochromes reveals opposite functionalities in two-component signaling
2021
Bacterial phytochrome photoreceptors usually belong to two-component signaling systems which transmit environmental stimuli to a response regulator through a histidine kinase domain. Phytochromes switch between red light-absorbing and far-red light-absorbing states. Despite exhibiting extensive structural responses during this transition, the model bacteriophytochrome from Deinococcus radiodurans (DrBphP) lacks detectable kinase activity. Here, we resolve this long-standing conundrum by comparatively analyzing the interactions and output activities of DrBphP and a bacteriophytochrome from Agrobacterium fabrum (Agp1). Whereas Agp1 acts as a conventional histidine kinase, we identify DrBphP a…
Metal complex-DNA binding: Insights from molecular dynamics and DFT/MM calculations.
2012
Molecular dynamics (MD) simulations, followed by density functional theory/molecular mechanics (DFT/MM) calculations, provided a detailed structure of the binding site between the cationic metallointercalator (dipyrido [3,2-a:2',3'-c]phenazine)(glycinato)copper(II), [Cu(gly)(dppz)](+), and the two dodeca-deoxynucleotide duplexes [dodeca(dG-dC)]2 and [dodeca(dA-dT)]2. Three simultaneous DNA binding types were detected in the fully optimized DFT/MM structures: 1) metal coordination through exocyclic oxygen atoms of nitrogen bases; 2) intercalation of the dppz chromophore between stacked Watson-Crick AT-AT and GC-GC bases; and 3) hydrogen bonding between the glycinato ligand and amine groups o…