Search results for "QM"
showing 10 items of 284 documents
A Microscopic Description of SARS-CoV-2 Main Protease Inhibition with Michael Acceptors. Strategies for Improving Inhibitors Design
2020
The irreversible inhibition of the main protease of SARS-CoV-2 by a Michael acceptor known as N3 has been investigated using multiscale methods. The noncovalent enzyme–inhibitor complex was simulated using classical molecular dynamics techniques and the pose of the inhibitor in the active site was compared to that of the natural substrate, a peptide containing the Gln–Ser scissile bond. The formation of the covalent enzyme–inhibitor complex was then simulated using hybrid QM/MM free energy methods. After binding, the reaction mechanism was found to be composed of two steps: (i) the activation of the catalytic dyad (Cys145 and His41) to form an ion pair and (ii) a Michael addition where the …
Exploration of the Activation Mechanism of the Epigenetic Regulator MLL3: A QM/MM Study
2021
The mixed lineage leukemia 3 or MLL3 is the enzyme in charge of the writing of an epigenetic mark through the methylation of lysine 4 from the N-terminal domain of histone 3 and its deregulation has been related to several cancer lines. An interesting feature of this enzyme comes from its regulation mechanism, which involves its binding to an activating dimer before it can be catalytically functional. Once the trimer is formed, the reaction mechanism proceeds through the deprotonation of the lysine followed by the methyl-transfer reaction. Here we present a detailed exploration of the activation mechanism through a QM/MM approach focusing on both steps of the reaction, aiming to provide new…
In Silico Conformational Features of Botulinum Toxins A1 and E1 According to Intraluminal Acidification
2022
International audience; Although botulinum neurotoxins (BoNTs) are among the most toxic compounds found in nature, their molecular mechanism of action is far from being elucidated. A key event is the conformational transition due to acidification of the interior of synaptic vesicles, leading to translocation of the BoNT catalytic domain into the neuronal cytosol. To investigate these conformational variations, homology modeling and atomistic simulations are combined to explore the internal dynamics of the sub-types BoNT/A1 (the most-used sub-type in medical applications) and BoNT/E1 (the most kinetically efficient sub-type). This first simulation study of di-chain BoNTs in closed and open s…
Mitochondrial DNA copy number and telomere length in peripheral blood mononuclear cells in comparison with whole blood in three different age groups
2019
There are more and more studies on telomere length (TL) and mitochondrial DNA (mtDNA), and it has been proven that these factors play a significant role in the aging of the immune system thereby it is important to understand how it varies in different cell types for more accurate conclusions. The aim of this study was to look into dynamics of mtDNA amount in conjunction with TL in peripheral blood mononuclear cells (PBMC) during aging in comparison with whole blood (WB) cells. Overall, 53 samples were divided into three age groups: 20-39 year age group, 40-59 year age group and 60-79 year age group. MtDNA amount was determined by qPCR TaqMan, and TL was measured by Southern blotting of term…
Comparison of Methods for the Assessment of Nonlinearity in Short-Term Heart Rate Variability under different Physiopathological States
2019
Despite the widespread diffusion of nonlinear methods for heart rate variability (HRV) analysis, the presence and the extent to which nonlinear dynamics contribute to short-term HRV are still controversial. This work aims at testing the hypothesis that different types of nonlinearity can be observed in HRV depending on the method adopted and on the physiopathological state. Two entropy-based measures of time series complexity (normalized complexity index, NCI) and regularity (information storage, IS), and a measure quantifying deviations from linear correlations in a time series (Gaussian linear contrast, GLC), are applied to short HRV recordings obtained in young (Y) and old (O) healthy su…
MYD88 L265P mutation and interleukin‐10 detection in cerebrospinal fluid are highly specific discriminating markers in patients with primary central …
2021
Reliable biomarkers are needed to avoid diagnostic delay and its devastating effects in patients with primary central nervous system (CNS) lymphoma (PCNSL). We analysed the discriminating sensitivity and specificity of myeloid differentiation primary response (88) (MYD88) L265P mutation (mut-MYD88) and interleukin-10 (IL-10) in cerebrospinal fluid (CSF) of both patients with newly diagnosed (n = 36) and relapsed (n = 27) PCNSL and 162 controls (118 CNS disorders and 44 extra-CNS lymphomas). The concordance of MYD88 mutational status between tumour tissue and CSF sample and the source of ILs in PCNSL tissues were also investigated. Mut-MYD88 was assessed by TaqMan-based polymerase chain reac…
Motor Activity Improves Temporal Expectancy
2015
International audience; Certain brain areas involved in interval timing are also important in motor activity. This raises the possibility that motor activity might influence interval timing. To test this hypothesis, we assessed interval timing in healthy adults following different types of training. The pre- and post-training tasks consisted of a button press in response to the presentation of a rhythmic visual stimulus. Alterations in temporal expectancy were evaluated by measuring response times. Training consisted of responding to the visual presentation of regularly appearing stimuli by either: (1) pointing with a whole-body movement, (2) pointing only with the arm, (3) imagining pointi…
Kinematic analysis of motor strategies in frail aged adults during the Timed Up and Go: how to spot the motor frailty?
2015
Asma Hassani,1 Alexandre Kubicki,2,3 Vincent Brost,1 France Mourey,2,4 Fan Yang1 1Laboratoire LE2I CNRS 6306, Université de Bourgogne, Dijon, France; 2Institut National de la Santé et de la Recherche Médicale (INSERM), Cognition Action et Plasticité Sensori-Motrice, Campus Universitaire, Université de Bourgogne, Dijon, France; 3Centre Hospitalier Universitaire de Dijon, Hôpital de Champmaillot, Dijon, France; 4Faculté de Médecine, Université de Bourgogne, Dijon, France Objective: The purpose of this work was to analyze and compare the movement kinematics of sit-to-stand (STS) and back-to-sit (B…
RGD-mimic polyamidoamine-montmorillonite composites with tunable stiffness as scaffolds for bone tissue-engineering applications
2017
This paper reports on the development of montmorillonite (MMT)-reinforced hydrogels, based on a peptidomimetic polyamidoamine carrying guanidine pendants (AGMA1), as substrates for the osteo-induction of osteoblast precursor cells. AGMA1 hydrogels of various degrees of crosslinking responded favourably to MMT reinforcement, giving rise to composite hydrogels with shear storage modulus G', when fully swollen in water, up to 200 kPa, i.e. 20 times higher than the virgin hydrogels and of the same order or higher than other hydrogel-based composites proposed for orthopaedic applications. This significant improvement was ascribed to the effective interpenetration between the polymer matrix and t…
FT-Raman and QM/MM study of the interaction between histamine and DNA
2006
The interaction between histamine and highly polymerized calf-thymus DNA has been investigated using FT-Raman spectroscopy and the hybrid QM/MM (quantum mechanics/molecular mechanics) methodology. Raman spectra of solutions containing histamine and calf-thymus DNA, at different molar ratios, were recorded. Solutions were prepared at physiological settings of pH and ionic strength, using both natural and heavy water as the solvent. The analysis of the spectral changes on the DNA Raman spectra when adding different concentrations of histamine allowed us to identify the reactive sites of DNA and histamine, which were used to built two minor groove and one intercalated binding models. They were…