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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.

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).

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.

Tarek M.,CNRS Structure and Reactivity of Complex Molecular Systems | Delemotte L.,CNRS Structure and Reactivity of Complex Molecular Systems | Delemotte L.,Temple University
Accounts of Chemical Research | Year: 2013

Ion channels conduct charged species through otherwise impermeable biological membranes. Their activity supports a number of physiological processes, and genetic mutations can disrupt their function dramatically. Among these channels, voltage gated cation channels (VGCCs) are ubiquitous transmembrane proteins involved in electrical signaling. In addition to their selectivity for ions, their function requires membrane-polarization-dependent gating.Triggered by changes in the transmembrane voltage, the activation and deactivation of VGCCs proceed through a sensing mechanism that prompts motion of conserved positively charged (basic) residues within the S4 helix of a four-helix bundle, the voltage sensor domain (VSD). Decades of experimental investigations, using electrophysiology, molecular biology, pharmacology, and spectroscopy, have revealed details about the function of VGCCs. However, in 2005, the resolution of the crystal structure of the activated state of one member of the mammalian voltage gated potassium (Kv) channels family (the Kv1.2) enabled researchers to make significant progress in understanding the structure-function relationship in these proteins on a molecular level. In this Account, we review the use of a complementary technique, molecular dynamics (MD) simulations, that has offered new insights on this timely issue.Starting from the "open-activated state" crystal structure, we have carried out large-scale all atom MD simulations of the Kv1.2 channel embedded in its lipidic environment and submitted to a hyperpolarizing (negative) transmembrane potential. We then used steered MD simulations to complete the full transition to the resting-closed state. Using these procedures, we have followed the operation of the VSDs and uncovered three intermediate states between their activated and deactivated conformations. Each conformational state is characterized by its network of salt bridges and by the occupation of the gating charge transfer center by a specific S4 basic residue. Overall, the global deactivation mechanism that we have uncovered agrees with proposed kinetic models and recent experimental results that point towards the presence of several intermediate states.The understanding of these conformations has allowed us to examine how mutations of the S4 basic residues analogous to those involved in genetic diseases affect the function of VGCCs. In agreement with electrophysiology experiments, mutations perturb the VSD structure and trigger the appearance of state-dependent "leak" currents. The simulation results unveil the key elementary molecular processes involved in these so-called "omega" currents. We generalize these observations to other members of the VGCC family, indicating which type of residues may generate such currents and which conditions might cause leaks that prevent proper function of the channel.Today, the understanding of the intermediate state conformations enables researchers to confidently tackle other key questions such as the mode of action of toxins or modulation of channel function by lipids. © 2013 American Chemical Society.

Schmidtke P.,University of Barcelona | Bidon-chanal A.,CNRS Structure and Reactivity of Complex Molecular Systems | Luque F.J.,University of Barcelona | Barril X.,University of Barcelona | Barril X.,Catalan Institution for Research and Advanced Studies
Bioinformatics | Year: 2011

Motivation: A variety of pocket detection algorithms are now freely or commercially available to the scientific community for the analysis of static protein structures. However, since proteins are dynamic entities, enhancing the capabilities of these programs for the straightforward detection and characterization of cavities taking into account protein conformational ensembles should be valuable for capturing the plasticity of pockets, and therefore allow gaining insight into structure-function relationships.Results: This article describes a new method, called MDpocket, providing a fast, free and open-source tool for tracking small molecule binding sites and gas migration pathways on molecular dynamics (MDs) trajectories or other conformational ensembles. MDpocket is based on the fpocket cavity detection algorithm and a valuable contribution to existing analysis tools. The capabilities of MDpocket are illustrated for three relevant cases: (i) the detection of transient subpockets using an ensemble of crystal structures of HSP90; (ii) the detection of known xenon binding sites and migration pathways in myoglobin; and (iii) the identification of suitable pockets for molecular docking in P38 Map kinase. © The Author 2011. Published by Oxford University Press. All rights reserved.

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.

Monari A.,CNRS Structure and Reactivity of Complex Molecular Systems | Rivail J.-L.,CNRS Structure and Reactivity of Complex Molecular Systems | Assfeld X.,CNRS Structure and Reactivity of Complex Molecular Systems
Accounts of Chemical Research | Year: 2013

Molecular mechanics methods can efficiently compute the macroscopic properties of a large molecular system but cannot represent the electronic changes that occur during a chemical reaction or an electronic transition. Quantum mechanical methods can accurately simulate these processes, but they require considerably greater computational resources. Because electronic changes typically occur in a limited part of the system, such as the solute in a molecular solution or the substrate within the active site of enzymatic reactions, researchers can limit the quantum computation to this part of the system. Researchers take into account the influence of the surroundings by embedding this quantum computation into a calculation of the whole system described at the molecular mechanical level, a strategy known as the mixed quantum mechanics/molecular mechanics (QM/MM) approach.The accuracy of this embedding varies according to the types of interactions included, whether they are purely mechanical or classically electrostatic. This embedding can also introduce the induced polarization of the surroundings. The difficulty in QM/MM calculations comes from the splitting of the system into two parts, which requires severing the chemical bonds that link the quantum mechanical subsystem to the classical subsystem. Typically, researchers replace the quantoclassical atoms, those at the boundary between the subsystems, with a monovalent link atom. For example, researchers might add a hydrogen atom when a C-C bond is cut.This Account describes another approach, the Local Self Consistent Field (LSCF), which was developed in our laboratory. LSCF links the quantum mechanical portion of the molecule to the classical portion using a strictly localized bond orbital extracted from a small model molecule for each bond. In this scenario, the quantoclassical atom has an apparent nuclear charge of +1. To achieve correct bond lengths and force constants, we must take into account the inner shell of the atom: for an sp3 carbon atom, we consider the two core 1s electrons and treat that carbon as an atom with three electrons. This results in an LSCF+3 model. Similarly, a nitrogen atom with a lone pair of electrons available for conjugation is treated as an atom with five electrons (LSCF+5). This approach is particularly well suited to splitting peptide bonds and other bonds that include carbon or nitrogen atoms.To embed the induced polarization within the calculation, researchers must use a polarizable force field. However, because the parameters of the usual force fields include an average of the induction effects, researchers typically can obtain satisfactory results without explicitly introducing the polarization. When considering electronic transitions, researchers must take into account the changes in the electronic polarization. One approach is to simulate the electronic cloud of the surroundings by a continuum whose dielectric constant is equal to the square of the refractive index. This Electronic Response of the Surroundings (ERS) methodology allows researchers to model the changes in induced polarization easily. We illustrate this approach by modeling the electronic absorption of tryptophan in human serum albumin (HSA). © 2012 American Chemical Society.

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.

Khalfa A.,CNRS Structure and Reactivity of Complex Molecular Systems | Tarek M.,CNRS Structure and Reactivity of Complex Molecular Systems
Journal of Physical Chemistry B | Year: 2010

[RRKWLWLW] cyclic peptides have been shown to exhibit remarkable in vitro and in vivo antibacterial activity. Peptides alike seem to be promising for the development of new compounds to combat microbial pathogens, yet the molecular level understanding of their mechanism of action remains unclear. Here, we use coarse-grained (CG) molecular dynamics (MD) simulations of these cyclic peptides interacting with antibacterial cytoplasmic membrane models composed of a mixture of palmitoyl-oleoyl-phosphatidyl-ethanolamine (POPE) and palmitoyl-oleoyl-phosphatidylglycerol (POPG) lipid bilayers to provide a better understanding of their mode of action. In particular, the MD simulations performed at various concentrations of membrane-bound cyclic peptides reveal a novel type of mechanism in which the peptides first self-assemble at the membrane interface into amphipathic nanotubes. At high enough concentrations, coating of the membrane causes extrusion of lipids from the exposed bilayer leaflet, leading ultimately to a release of phospholipid micellar aggregates. Furthermore, the cyclic peptides also induce a drastic change in the lateral pressure profiles of the exposed leaflet, indicating a direct effect on the mechanical properties of the bilayer. © 2010 American Chemical Society.

Chantzis A.,CNRS Structure and Reactivity of Complex Molecular Systems | Very T.,CNRS Structure and Reactivity of Complex Molecular Systems | Monari A.,CNRS Structure and Reactivity of Complex Molecular Systems | Assfeld X.,CNRS Structure and Reactivity of Complex Molecular Systems
Journal of Chemical Theory and Computation | Year: 2012

The UV/vis and circular-dichroism spectra of a bis-bipyridinyl ruthenium complex are computed at the density functional theory level and the time dependent density functional level of theory. The effects of the solvent, here water, have been taken into account, by polarizable continuum methods and by a hybrid quantum-mechanics/molecular-mechanics approach combined with molecular dynamics. The effects of the solvent have been decomposed in geometric, electrostatic, and polarization of the environment. The principal transitions have been analyzed by means of natural transition orbitals. © 2012 American Chemical Society.

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