65 research outputs found
Rétrotransposons et cellules somatiques
No full textLes éléments transposables sont des séquences d’ADN endogènes mobiles constituant environ 40 % du génome humain. D’abord reconnus comme actifs dans les cellules germinales adultes, il apparaît qu’ils ont aussi une activité de transposition élevée dans les cellules somatiques. Leur implication directe dans les mécanismes oncogéniques s’avère cruciale dans la dérégulation de l’expression génique normale. De nouveaux mécanismes de régulation de leur expression ont été découverts montrant que leur silencing, par l’intermédiaire de modifications épigénétiques, dépend de gènes suppresseurs de tumeur
Perspective: Ab initio force field methods derived from quantum mechanics
No full textIt is often desirable to accurately and efficiently model the behavior of large molecular systems in the condensed phase (thousands to tens of thousands of atoms) over long time scales (from nanoseconds to milliseconds). In these cases, ab initio methods are difficult due to the increasing computational cost with the number of electrons. A more computationally attractive alternative is to perform the simulations at the atomic level using a parameterized function to model the electronic energy. Many empirical force fields have been developed for this purpose. However, the functions that are used to model interatomic and intermolecular interactions contain many fitted parameters obtained from selected model systems, and such classical force fields cannot properly simulate important electronic effects. Furthermore, while such force fields are computationally affordable, they are not reliable when applied to systems that differ significantly from those used in their parameterization. They also cannot provide the information necessary to analyze the interactions that occur in the system, making the systematic improvement of the functional forms that are used difficult. Ab initio force field methods aim to combine the merits of both types of methods. The ideal ab initio force fields are built on first principles and require no fitted parameters. Ab initio force field methods surveyed in this perspective are based on fragmentation approaches and intermolecular perturbation theory. This perspective summarizes their theoretical foundation, key components in their formulation, and discusses key aspects of these methods such as accuracy and formal computational cost. The ab initio force fields considered here were developed for different targets, and this perspective also aims to provide a balanced presentation of their strengths and shortcomings. Finally, this perspective suggests some future directions for this actively developing area.This article may be downloaded for personal use only. Any other use requires prior permission of the author and AIP Publishing. This article appeared in Xu, Peng, Emilie B. Guidez, Colleen Bertoni, and Mark S. Gordon. "Perspective: Ab initio force field methods derived from quantum mechanics." The Journal of Chemical Physics 148, no. 9 (2018): 090901, and may be found at DOI: 10.1063/1.5009551. Copyright 2018 Author(s). Posted with permission
Histone deacetylase 9
No full textThe identification and cloning of histone deacetylase 9 (HDAC9) is disclosed, and in particular full length HDAC9 polypeptides and HDAC9 polypeptides which have deacetylase activity, and to nucleic acid molecules encoding these polypeptides. The uses of these polypeptides and nucleic acid molecules are disclosed, for example for screening for compounds that are capable of modulating a HDAC9 biological activity
Computation of host–guest binding free energies with a new quantum mechanics based mining minima algorithm
No full textA new method called QM-VM2 is presented that efficiently combines statistical mechanics with quantum mechanical (QM) energy potentials in order to calculate noncovalent binding free energies of host–guest systems. QM-VM2 efficiently couples the use of semi-empirical QM (SEQM) energies and geometry optimizations with an underlying molecular mechanics (MM) based conformational search, to find low SEQM energy minima, and allows for processing of these minima at higher levels of ab initio QM theory. A progressive geometry optimization scheme is introduced as a means to increase conformational sampling efficiency. The newly implemented QM-VM2 is used to compute the binding free energies of the host molecule cucurbit[7]uril and a set of 15 guest molecules. The results are presented along with comparisons to experimentally determined binding affinities. For the full set of 15 host–guest complexes, which have a range of formal charges from +1 to +3, SEQM-VM2 based binding free energies show poor correlation with experiment, whereas for the ten +1 complexes only, a significant correlation (R2 = 0.8) is achieved. SEQM-VM2 generation of conformers followed by single-point ab initio QM calculations at the dispersion corrected restricted Hartree–Fock-D3(BJ) and TPSS-D3(BJ) levels of theory, as post-processing corrections, yields a reasonable correlation with experiment for the full set of host–guest complexes (R2 = 0.6 and R2 = 0.7, respectively) and an excellent correlation for the +1 formal charge set (R2 = 1.0 and R2 = 0.9, respectively), as long as a sufficiently large basis set (triple-zeta quality) is employed. The importance of the inclusion of configurational entropy, even at the MM level, for the achievement of good correlation with experiment was demonstrated by comparing the calculated ΔE values with experiment and finding a considerably poorer correlation with experiment than for the calculated free energy ΔE − TΔS. For the complete set of host–guest systems with the range of formal charges, it was observed that the deviation of the predicted binding free energy from experiment correlates somewhat with the net charge of the systems. This observation leads to a simple empirical interpolation scheme to improve the linear regression of the full set.This article may be downloaded for personal use only. Any other use requires prior permission of the author and AIP Publishing. This article appeared in Xu, Peng, Tosaporn Sattasathuchana, Emilie Guidez, Simon P. Webb, Kilinoelani Montgomery, Hussna Yasini, Iara FM Pedreira, and Mark S. Gordon. "Computation of host–guest binding free energies with a new quantum mechanics based mining minima algorithm." The Journal of Chemical Physics 154, no. 10 (2021): 104122, and may be found at DOI: 10.1063/5.0040759. Copyright 2022 Author(s). Posted with permission
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Reduced Retinoic Acid-Sensitivities of Nuclear Receptor Corepressor Binding to PML- and PLZF-RARα Underlie Molecular Pathogenesis and Treatment of Acute Promyelocytic Leukemia
No full textTypical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARα fusion protein and responsiveness to treatment with all-trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARα fusion protein. Both PML- and PLZF-RARα possess identical RAR sequences and inhibit ATRA-induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARα protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARα, it had a very little effect on its association with the PLZF-RARα fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARα was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARα fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARα on ATRA response. Taken together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARα–associated leukemias to ATRA
HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements.
No full textFor the past decade protein acetylation has been shown to be a crucial post-transcriptional modification involved in the regulation of protein functions. Histone acetyltransferases (HATs) mediate acetylation of histones which results in the nucleosomal relaxation associated with gene expression. The reverse reaction, histone deacetylation, is mediated by histone deacetylases (HDACs) leading to chromatin condensation followed by transcriptional repression. HDACs are divided into distinct classes: I, IIa, IIb, III and IV, on the basis of size and sequence homology, as well as formation of distinct repressor complexes. Implications of HDACs in many diseases, such as cancer, heart failure and neurodegeneration, have identified these molecules as unique and attractive therapeutic targets. The emergence of HDAC4 among the members of class IIa family as a major player in synaptic plasticity raises important questions about its functions in the brain. The characterization of HDAC4 specific substrates and molecular partners in the brain will not only provide a better understanding of HDAC4 biological functions but also might help to develop new therapeutic strategies to target numerous malignancies. In this review we highlight and summarize recent achievements in understanding the biological role of HDAC4 in neurodegenerative processes
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