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Prediction/Calculation of Protein-Protein Binding Affinities And Mutation Effects

• Sébastien Fiorucci , Serge Antonczak, Jérôme Golebiowski,
  in
  Protein-protein complexes: Analysis, modeling and drug design , ed. M. Zacharias, Imperial Press, 2009
  (voir ici)
  

Given the immense progress achieved in elucidating protein–protein complex structures and in the field of protein interaction modeling, there is great demand for a book that gives interested researchers/students a comprehensive overview of the field. This book does just that. It focuses on what can be learned about protein–protein interactions from the analysis of protein–protein complex structures and interfaces. What are the driving forces for protein–protein association? How can we extract the mechanism of specific recognition from studying protein–protein interfaces? How can this knowledge be used to predict and design protein–protein interactions (interaction regions and complex structures)? What methods are currently employed to design protein–protein interactions, and how can we influence protein–protein interactions by mutagenesis and small-molecule drugs or peptide mimetics?

This chapter reviews the most common theoretical methods to compute protein-protein binding affinities and relative free energies due to residue mutation. The approaches described range from alchemical mutations,
like free energy perturbation or thermodynamic integration to knowledge-based method, through LIE and MMPBSA calculations.

See S Fiorucci home page for further informations

Prediction of protein-protein interaction sites using electrostatic desolvation profiles.

• S. Fiorucci, M. Zacharias,
  Biophys. Journal, accepté, 2010

Protein-protein complex formation involves removal of water from the interface region. Surface regions with a small free energy penalty for water removal or desolvation may correspond to preferred interaction sites. A method to calculate the electrostatic free energy of placing a neutral low dielectric probe at various protein surface positions has been designed and applied to characterize putative interaction sites. Based on solutions of the finite-difference Poisson equation it includes also long range electrostatic contributions and the protein solvent boundary shape in contrast to accessible surface area based solvation energies. Calculations on a large set of proteins indicate that in the majority of cases (>90%) the known protein binding site overlaps with one of the six regions of lowest electrostatic desolvation penalty (overlap with the lowest desolvation region for 48% of proteins). Since the onset of electrostatic desolvation occurs already before direct protein-protein contact formation it may help guiding proteins toward the binding region in the final stage of complex formation. Interestingly, the probe desolvation properties associated with residue types was found to depend on if the residue was outside or part of a binding site. Especially for aromatic residues but also for some polar residues the probe desolvation penalty was on average significantly smaller if the residue was part of a binding site compared to other surface locations. Applications to several antigen-antibody complexes demonstrated that the approach might not only be useful to predict protein interaction sites in general but could also be useful to map potential antigenic epitopes on protein surfaces.

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Ab Initio Study of Alkylation of Guanine-Cytosine Base Pair by Sulfur and Nitrogen Mustards

• Dan Vasilescu, Martine Adrian–Scotto, Ahmed Fadiel, Adel Hamza
  Journal of Biomolecular Structure & Dynamics, 2010, Volume 27,
  Issue 4, 465-476.

Quantum modeling of the N7(G) alkylation of guanine-cytosine (G-C) base pair by sulfur (HD) and nitrogen mustard (HN2) was performed by using the Density Functional Theory (DFT) BPW91/6-31G++DP procedure. The vibrational IR and Raman spectra are discussed with regard to the N7 position of guanine when electrophilic HD+ episulfonium and HN2+ aziridinium attack the G-C base pair. Thermodynamic and polarizability considerations are also presented. The computed electronic chemical potential and the electrophilicity of the studied
species indicate that an electronic transfer is produced from the nucleophile (G-C) base pair to the electrophile HD+ episulfonium or HN2+ aziridinium during the alkylation process.

Design, synthesis and studies of triphosphate analogues for the production of anti AZT-TP antibodies.

• Camille Roucairol, Stéphane Azoulay, Marie-Claire Nevers, Jérôme Golebiowski, Christophe Créminon, Jacques Grassi, Alain Burger, Danièle Duval
  Bioorganic & Medicinal Chemistry Letters, 2010, 20, 987–990.

Triphosphates anabolites are the active chemical species of nucleosidic reverse transcriptase inhibitors in
HIV-therapy. Herein, we describe (i) the design of stable triphosphate analogues of AZT using molecular
modelling, (ii) their synthesis and (iii) their use for producing anti AZT-TP antibodies in the aim of developing
an immunoassay for therapeutic drug monitoring.

Theoretical Investigations of the Role Played by Quercetinase Enzymes upon Flavonoids Oxygenolysis Mechanism.

• Serge Antonczak, Sébastien Fiorucci , Jérôme Golebiowski, Daniel Cabrol-Bass
  PCCP, 2009,  volume 11 , 1491-1501
  
  

Quercetinase enzymatic activity consists in the addition of dioxygen onto flavonoids, some natural polyphenol compounds, leading to the production of both molecular carbon monoxide and to the structurally related depside compound. Experimental studies have reported degradation rates of various flavonoids by such enzymes that can not be directly correlated neither to the number nor to the place of the hydroxyl groups. In order to decipher the role of these functions, we have theoretically characterized the stationary points of various flavonoids oxygenolysis mechanisms by Density Functional quantum methods. Thus in the present study are reported the main energetic, structural and electronic features that drive this degradation. Together with previous analysis from MD simulations taking into account the dynamic behaviour of the substrate embedded in the enzyme cavity, the present results show that the role of the enzyme, in terms of structural and electronic effects, can not be neglected. Thus, we propose here that deformations of the substrate induced by the enzyme could originate the differences in the degradation rates experimentally observed.

See S. Antonczak home page for further informations

PTools: an opensource molecular docking library.

• Adrien Saladin, Sébastien Fiorucci, Pierre Poulain, Chantal Prevost and Martin Zacharias, BMC Structural Biology, 2009 , 9, 27

Macromolecular docking is a challenging field of bioinformatics. Developing new algorithms is a slow process generally involving routine tasks that should be found in a robust library and not programmed from scratch for every new software application. We present an object-oriented Python/C++ library to help the development of new docking methods. This library contains low-level routines like PDB-format manipulation functions as well as high-level tools for docking and analyzing results. We also illustrate the ease of use of this library with the detailed implementation of a 3-body docking procedure. The PTools library can handle molecules at coarse-grained or atomic resolution and allows users to rapidly develop new software. The library is already in use for protein-protein and protein-DNA docking with the ATTRACT program and for simulation analysis. This library is freely available under the GNU GPL license, together with detailed documentation.

See S Fiorucci home page for further informations

How does human odorant binding protein bind odorants ? The case of aldehydes studied by molecular dynamics.

• Landry Charlier , Daniel Cabrol-Bass, Jérome Golebiowski , Compte Rendus Chimie, 2009 , 12, 905-910.
  
  

Human Odorant Binding Protein (OBP IIa) has a strong affinity for odorants belonging to the family of aldehydes. After having built the initial structures based on the protein sequence, we have performed molecular dynamics simulations on human-OBP, free and bound to citral and undecanal to examine the reasons for this affinity from a dynamic point of view. The formation of a Schiff base between a Lysine residue and the aldehyde function could be responsible for this strong affinity.

See J. Golebiowski home page for further informations

Deciphering the selectivity of Bombyx mori Pheromone Binding
Protein for Bombykol over Bombykal. A theoretical approach.

• Landry Charlier, Serge Antonczak, Emmanuelle Jacquin-Joly, Daniel Cabrol-Bass, Jérôme Golebiowski, ChemPhysChem, 2008 , 9, 2785-2793

In this article we report calculations dedicated to estimate the selectivity of the Bombyx mori
Pheromone Binding Protein towards the two closely related pheromonal components Bombykol and
Bombykal. The selectivity is quantified by the binding free energy difference, obtained either by the
Thermodynamic Integration or by the MM-GBSA approach. In the latter, the selectivity is
decomposed on a per-residue basis, allowing to identify the residues considered as crucial for the
selectivity of the protein for Bombykol over Bombykal. A discussion on the role of Bombyx mori
Pheromone Binding Protein is provided on the basis of these results.

See J. Golebiowski home page for further informations

Molecular simulations enlighten the binding mode of quercetin to lipoxygenase-3.

• Serge Antonczak , Sébastien Fiorucci, Jérôme Golebiowski, Daniel Cabrol-Bass, Proteins-Structure, Function and Bioinformatics, 2008, Volume 73, Issue 2, 290-298
  

Inhibition of lipoxygenases by flavonoid compounds is now well documented but the description of the associated mechanism remains controversial due to a lack of information at the molecular level. For instance, X-Ray determination of quercetin/LOX-3 system has led to a structure where the enzyme was co-crystallized with a degradation product of the substrate rendering then difficult the interpretation of the reported interactions between this flavonoid compound and the enzyme. Molecular Modelling simulations can in principle allow obtaining precious insights that could fill this lack of structural information. Thus, in the present study, we have investigated various binding modes of quercetin to LOX-3 enzyme in order to understand the first step of the inhibition process, i.e. the association of the two entities. Molecular dynamics simulations and free energy calculations suggest that quercetin binds the metal centre via its 3-hydroxychromone function. Moreover, enzyme/substrate interactions within the cavity impose steric hindrances to quercetin that may activate a direct dioxygen addition on the substrate.

See S. Antonczak home page for further informations

Quantum Molecular Modeling of Glycyl-Adenylate

• Martine Adrian-Scotto, Dan Vasilescu , JBSD, 2008 , Volume 25 No. 6 (p 573-752)
  

Glycyl-adenylate is the simplest model for understanding the central role played by aminoacyl-adenylates in the protein synthesis, and may be also in the prebiotic evolution. Optimized conformation of glycyl-adenylate (GlyAMP), in vacuum, was determined using ab initio RHF/6-31Gdp computations. GlyAMP in vacuum (form corresponding to neutral pH conditions) possesses a specific conformation of the glycyl-phosphate stem with a double seven membered ring that results from the electrostatic interaction between the anionic phosphate and the cationic ammonium. This structure is explained on the basis of the theoretical infrared vibrational spectrum and discussed with regard to those of glycyl-adenylate (GAP1550 and GAP2550 forms) in the active pockets of glycyl-tRNA synthetase. The electrostatic properties of these different conformations are presented, and the influence of the charged residues (anionic GLU188, GLU239, GLU359, and cationic ARG220) and Mg ++ , in interaction with GAP1550 are discussed, taking into account the computation of the electronic chemical potential, the electron affinity and the electrophilic index.

See M. Adrian-Scotto home page for further informations

Electronic description of four flavonoids revisited by DFT method

• Serge Antonczak , J. Mol. Struc. Theochem, 2008, 856, 38-45 doi:10.1016/j.theochem.2008.01.014

Structural and electronic characteristics of four flavonoids, namely quercetin, luteolin, catechin and taxifolin, have been revisited by means of B3LYP density functional. Rotation energy of the catechol moieties together with HOMO–LUMO, dipole moments analyses are reported for each flavonoid. Deprotonation and hydrogen abstraction energies of the O3H and O4'H hydroxyl groups are compared and analyzed with the help of an electronic description for each structure. Our results put forward the significant role of p-delocalization upon stabilization but have also shown that inductive effects play a major role in the stabilization of deprotonated forms. Inspection of the charge transfer together with analysis of a simple model of catechol has also demonstrated the relative independence of each structural motif when hydrogen abstraction processes are considered

See S. Antonczak home page for further informations

Binding free energy prediction in strongly hydrophobic biomolecular systems

• Landry Charlier, Claude Nespoulous, Sébastien Fiorucci, Serge Antonczak and Jérome Golebiowski , PCCP, 2007 , DOI: 10.1039/b710186d
  
  >>>go to PCCP>>>

See J. Golebiowski home page for further informations

Molecular simulations bring new insights into flavonoid/quercetinase interaction modes.

• Sébastien Fiorucci, Jérôme Golebiowski, Daniel Cabrol-Bass, Serge Antonczak , Proteins-Structure, Function and Bioinformatics, 2007 , 67(4), 961-970

(go to Proteins)

Molecular dynamics simulations, using the AMBER force field, were performed to study Quercetin 2,3-Dioxygenase enzyme (Quercetinase or 2,3QD). We have analyzed the structural modifications of the active site and of the linker region between the native enzyme and the enzyme-substrate complex. New structural informations, such as an allosteric effect in the presence of the substrate, as well as description of the enzyme-substrate interactions and values of binding free energies were brought out. All these results confirm the idea that the linker encloses the substrate in the active site and also enlighten the recognition role of the substrate B-ring by the enzyme. Moreover, a specific interaction scheme has been proposed to explain the relative degradation rate of various flavonoid compounds under the oxygenolysis reaction catalyzed by the Quercetin 2,3-Dioxygenase enzyme

See S. Antonczak home page for further informations

Mechanistic events underlying odorant binding protein chemoreception

• Jérôme Golebiowski, Serge Antonczak, Sébastien Fiorucci, Daniel Cabrol-Bass , Proteins-Structure, Function and Bioinformatics, 2007 , 67(2), 448-458.

Odorant binding proteins (OBP's) are small hydrophilic proteins, belonging to the lipocalin family dedicated to bind and transport small hydrophobic ligands. Despite many works, the mechanism of ligand binding, together with the functional role of these proteins remains a topic of debate and little is known at the atomic level. The present work reports a computational study of odorants capture and release by an OBP, using both constrained and unconstrained simulations, giving a glimpse on the molecular mechanism of chemoreception. The residues at the origin of the regulation of the protein door opening are identified and a tyrosine amino-acid together with other nearby residues appear to play a crucial role in allowing this event to occur. The simulations reveal that this tyrosine and the protein's L5 loop are implicated in the ligand contact with the protein and act as an anchoring point for the ligand. The protein structural features required for the ligand entry are highly conserved among many transport proteins, suggesting that this mechanism could somewhat be extended to some members of the larger family of lipocalin.

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Cerium(IV)-mediated oxidation of flavonol with relevance to flavonol 2,4-dioxygenase. Direct evidence for spin delocalization in the flavonoxy radical

• József Kaizer, Ildikó Ganszky, Gábor Speier, Antal Rockenbauer, László Korecz, Michel Giorgi, Marius Réglier and Serge Antonczak, Journal of Inorganic Biochemistry, 2007 , 101(6), 893-899
  
  

The cerium(IV)-mediated oxidation of 3-hydroxy-4'-methylflavone ( 1 ) proceeds by H-atom abstraction forming the flavonoxy radical ( 7 ), and the subsequent combination of its resonance forms leads to the 3-hydroxy-4'-methylflavone dehydro dimer ( 9 ). The above system serves as direct evidence for the intermediacy of the flavonoxy radical, its spin delocalization, and also indirect evidence for valence tautomerism as a key step on the substrate activation both in the quercetinase and its biomimic model system.

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DFT Study of Quercetin Activated Forms Involved in Antiradical, Antioxidant, and Prooxidant Biological Processes

• Sébastien Fiorucci, Jérôme Golebiowski, Daniel Cabrol-Bass,and, and Serge Antonczak, Journal of Agricultural and Food Chemistry, 2007 , 55(3), 903-911.
  

Quercetin, one of the most representative flavonoid compounds, is involved in antiradical, antioxidant, and prooxidant biological processes. Despite a constant increase of knowledge on both positive and negative activities of quercetin, it is unclear which activated form (quinone, semiquinone, or deprotonated) actually plays a role in each of these processes. Structural, electronic, and energetic characteristics of quercetin, as well as the influence of a copper ion on all of these parameters, are studied by means of quantum chemical electronic structure calculations. Introduction of thermodynamic cycles together with the role of coreactive compounds, such as reactive oxygen species, gives a glimpse of the most probable reaction schemes. Such a theoretical approach provides another hint to clarify which reaction is likely to occur within the broad range of quercetin biological activities.

See S. Antonczak home page for further informations

Density functional theory study of (HCN) n clusters up to n  = 10

• Martine Adrian-Scotto and Dan Vasilescu, Journal of Molecular Structure: THEOCHEM ,  803 (1-3) , 45-60

Hydrogen cyanide is an extraterrestrial material which is also recognized today as a plausible prebiotic molecule of major interest about the origins of life.

This theoretical study is devoted to the quantum molecular modelling of HCN and (HCN) n clusters up to n  = 10, using the density functional theory method BPW91 with the large basis set 6-311G++3D3P. We have obtained the optimized geometries of linear clusters up to decamer and of cyclic trimer and tetramer, with the help of the vibrational frequencies method. Electrostatic properties (dipole moments, tensor of polarizabilities, molecular electrostatic potential), thermochemistry and vibrational spectra were computed.

For the linear clusters (HCN) n , the dipole moment and the polarizability show a linear variation versus n ; this behaviour implies a linear variation of the infrared intensity versus the Raman activity for the CH and the CN stretchings. The thermochemistry at T  = 298.15 K and P  = 1 atm of the linear polymerization (addition of HCN molecules each to other through hydrogen bonds) indicates that the reaction is exothermic (? H  < 0) but not spontaneous (? G  > 0 and ? S  < 0). The pure rotational lines of HCN in the far infrared band, detected by the recent Cassini-Huygens mission to Titan are interpreted through our obtained rotational constant for the HCN monomer.

See M. Adrian-Scotto home page for further informations

The marine sponge Plakortis zyggompha : a source of original bioactive polyketides

• Fabrice Berrue, Olivier P. Thomas, Remi Laville, Soizic Prado, Jerôme Golebiowski, Rogelio Fernandez and Philippe Amade, Tetrahedron, 2007, 63(10), 2328-2334

Molecular simulations reveal a new entry site in quercetin 2,3-dioxygenase. A pathway for dioxygen? 

• Sébastien Fiorucci, Jérôme Golebiowski, Daniel Cabrol-Bass, Serge Antonczak, Proteins-Structure, Function and Bioinformatics, 2006, 64(3), 845-850.

Molecular dynamics simulations performed on quercetin 2,3-dioxygenase have shown the existence of a channel linking the bulk solvent and the cavity of the enzyme. Although much is known about the the oxygenolysis reaction catalyzed by this enzyme, the way dioxygen enters the active site has not been firmly established. The size, orientation and hydrophobic character of this channel suggests that it could provide an entrance for molecular dioxygen into the cavity. Free energy calculations show that such a process is likely to occur.

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Density functional theory investigations on acid-catalysed epoxide oxidative ring-opening by DMSO. Competition between oxidation processes

• Sylvain Antoniotti, Jérôme Golebiowski , Daniel Cabrol-Bass and Elisabet Duñach, Journal of Molecular Structure: THEOCHEM ,  2006, 763 (1-3) ,  155-159 .

DFT investigations of the acid-catalysed oxidation of linear and cyclic epoxides by DMSO revealed that a first step of nucleophilic ring-opening is followed by two different reaction pathways: on one hand a-hydroxycarbonyl derivatives are formed, via oxidative ring-opening, and on the other hand two aldehyde moieties are obtained, via oxidative cleavage. Calculations with the polarized continuum method (PCM) taking into account the DMSO solvation effect did not significantly change the energy barriers.

Molecular dynamics studies of odorant binding protein free of ligand and complexed to pyrazine and octenol

• Jérôme Golebiowski , Serge Antonczak and Daniel Cabrol-Bass, Journal of Molecular Structure: THEOCHEM ,  2006, 763 (1-3) ,  165-174 .

The dynamic behaviour analysis of porcine OBP, free of ligand, and complexed with 2-isobutyl-3-methoxypyrazine and 2,6-dimethyl-7-octen-2-ol has been performed by means of molecular dynamics simulations. The simulations reveal that the OBP cavity, while being hydrophobic, is likely to produce hydrophilic interactions with some of the internal residues. A large evolution of the OBP cavity volume has been observed, ranging between 400 and 800 Å 3 independently of the ligand buried into the cavity. The hydrophobic cavity is shielded from the solvent, but openings have been observed, triggered by shifts of residues considered to constitute the door of the cavity, especially tyrosine 82.

See J. Golebiowski home page for further informations

Chemotaxonomic Study of ARTEMISA. An Approach Based on Multivariate Statistics of Skeletal Types Retrieved From Essential Oils

• C. Depege, L. Lizzani-Cuvelier, M. Loiseau, D. Cabrol-Bass, M.J.P. Ferreira, A.J.C. Brant, J.S.L.T. Militão, V.P.Emerenciano ,
  BLACPMA: Bulletin Latino Americano de Plantas Medicinales y Arommaticas ,  2006, 5(4),  72-83

This work describes the study of essential oils of some species of Artemisia based on statistical methods. The compositions of the essential oils of 48 plant species have been classified on the basis of their content with respect to the carbon skeletons of their constituents. Statistical techniques such as multiple linear regression, partial least square, principal component analysis and cluster analysis were used in the attempt of finding relationship correlations between the composition of the oils and the sections of the genus according to Ling’s classification.

Chemical evolution in the Asteraceae. The oxidation-reduction mechanism and production of secondary metabolites

• D. Cabrol-Bass, M.J.P. Ferreira, A.J.C. Brant, V.P. Emerenciano , Natural Product Communications, 2006 , 6 (1) 495-507 .