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Zou X.,University of Illinois at Urbana - Champaign | Ma W.,University of Illinois at Urbana - Champaign | Solov'Yov I.A.,University of Illinois at Urbana - Champaign | Chipot C.,University of Illinois at Urbana - Champaign | And 2 more authors.
Nucleic Acids Research | Year: 2012

DNA methylation is a key regulatory control route in epigenetics, involving gene silencing and chromosome inactivation. It has been recognized that methyl-CpG binding domain (MBD) proteins play an important role in interpreting the genetic information encoded by methylated DNA (mDNA). Although the function of MBD proteins has attracted considerable attention and is well characterized, the mechanism underlying mDNA recognition by MBD proteins is still poorly understood. In this article, we demonstrate that the methyl-CpG dinucleotides are recognized at the MBD-mDNA interface by two MBD arginines through an interplay of hydrogen bonding and cation-π interaction. Through molecular dynamics and quantum-chemistry calculations we investigate the methyl-cytosine recognition process and demonstrate that methylation enhances MBD-mDNA binding by increasing the hydrophobic interfacial area and by strengthening the interaction between mDNA and MBD proteins. Free-energy perturbation calculations also show that methylation yields favorable contribution to the binding free energy for MBD-mDNA complex. © 2011 The Author(s). Source


Kraszewski S.,University of Franche Comte | Tarek M.,CNRS Structure and Reactivity of Complex Molecular Systems | Ramseyer C.,University of Franche Comte
ACS Nano | Year: 2011

Bioactive molecules, cationic peptides among them, are nowadays well-recognized in modern pharmacology for their drug potential. However, they usually suffer from poor translocation across cell membranes, and specific drug carriers should be designed to circumvent this problem. In the present study, the uptake mechanism of fullerene bearing cationic ammonium groups by membranes modeled as lipid bilayers is investigated using extensive molecular dynamics simulations and free-energy calculations. Three main results issued from this work can be drawn. First, the fullerene core appears to be a good drug vector since it greatly enhances the uptake of the cationic groups by the membrane. Second, we show that the amino derivatives should be deprotonated at the lipid headgroup level in order to fully translocate the membrane by passive diffusion. Finally, the fullerenes bearing too many cationic groups display mostly a hydrophilic character; thus, the lipophilic fullerene core is not anymore effective as an insertion enhancer. Therefore, the lipid bilayer appears to be very selective with respect to the amount of amino groups conjugated with C 60. © 2011 American Chemical Society. Source


Gumbart J.C.,Argonne National Laboratory | Roux B.,Argonne National Laboratory | Roux B.,University of Chicago | Chipot C.,University of Illinois at Urbana - Champaign | Chipot C.,CNRS Structure and Reactivity of Complex Molecular Systems
Journal of Chemical Theory and Computation | Year: 2013

Accurate prediction of standard binding free energies describing protein-ligand association remains a daunting computational endeavor. This challenge is rooted to a large extent in the considerable changes in conformational, translational, and rotational entropies underlying the binding process that atomistic simulations cannot easily sample. In spite of significant methodological advances, reflected in a continuously improving agreement with experiment, a characterization of alternate strategies aimed at measuring binding affinities, notably their respective advantages and drawbacks, is somewhat lacking. Here, two distinct avenues to determine the standard binding free energy are compared in the case of a short, proline-rich peptide associating to the Src homology domain 3 of tyrosine kinase Abl. These avenues, one relying upon alchemical transformations and the other on potentials of mean force (PMFs), invoke a series of geometrical restraints acting on collective variables designed to alleviate sampling limitations inherent to classical molecular dynamics simulations. The experimental binding free energy of ΔGbind = -7.99 kcal/mol is well reproduced by the two strategies developed herein, with ΔGbind = -7.7 for the alchemical route and ΔGbind = -7.8 kcal/mol for the alternate PMF-based route. In detailing the underpinnings of these numerical strategies devised for the accurate determination of standard binding free energies, many practical elements of the proposed rigorous, conceptual framework are clarified, thereby paving way to tackle virtually any recognition and association phenomenon. © 2012 American Chemical Society. Source


Tilly D.,CNRS Chemistry Institute of Rennes | Chevallier F.,CNRS Chemistry Institute of Rennes | Mongin F.,CNRS Chemistry Institute of Rennes | Gros P.C.,CNRS Structure and Reactivity of Complex Molecular Systems
Chemical Reviews | Year: 2014

The special reactivity exhibited in halogen/metal exchange reactions when an alkali or alkaline earth metal compound is combined either with another alkali metal compound or with a compound containing a group 2 (Mg), group 6 (Cr), group 7 (Mn), group 11 (Cu), group 12 (Zn), or group 13 (In) element as acidic center, is studied. Spring and co-workers have investigated the bromine/metal exchange on polystyrene beads using various metalating agents. While BuLi or i-PrMgCl gave poor efficiencies, i-PrBu2MgLi was found to give complete bromine removal and excellent yields upon trapping with ClPPh2. Lida and co-workers reported the monosubstitution of dibromobenzenes, dibromopyridines, and dibromothiophenes using Bu 3MgLi. They found that it was possible to control the selectivity using 0.35 equiv of the reagent in a toluene-THF mixture. The approach developed by Knochel and co-workers was extended in 2009 to the synthesis of benzylic indium(III) reagents from the corresponding chlorides or bromides. Source


Genoni A.,CNRS Structure and Reactivity of Complex Molecular Systems
Journal of Physical Chemistry Letters | Year: 2013

Nowadays, the electron density is recognized as a fundamental property that contains most of the information concerning the electronic structure of molecules, and, therefore, its determination from high-resolution X-ray diffraction data is becoming more and more important. In this context, we propose a new strategy for the charge density analysis, strategy in which the chemical interpretability of the multipole model is combined with the quantum mechanical rigor of the wave function-based approaches. In particular, this novel technique aims at extracting molecular orbitals strictly localized on small molecular fragments (e.g., atoms, bonds, or functional groups) from a set of measured structure factors amplitudes. Preliminary tests have shown that their determination is really straightforward and, given their reliable transferability, we envisage the possibility of constructing new extremely localized molecular orbital databases as an alternative to the existing pseudoatom libraries. © 2013 American Chemical Society. Source

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