Nohad Gresh Laboratoire de Pharmacochimie Moléculaire et Cellulaire U648 INSERM UFR Biomédicale, Faculté de Médecine de Paris, France

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1 Perfectionnements et validation d une approche de mecanique moleculaire polarisable. Applications a des complexes d inhibiteurs avec des metalloproteines. Atelier CF Bio, Evry, 14 Mai 2007 Nohad Gresh Laboratoire de Pharmacochimie Moléculaire et Cellulaire U648 INSERM UFR Biomédicale, Faculté de Médecine de Paris, France Jean-Philip Piquemal Laboratoire de Chimie Théorique, Université Pierre-et- Marie-Curie,

2 Coauteurs: Benoit de Courcy, Michel Vidal, Wanq-Qing Liu, Christiane Garbay*; IFR Biomédicale, Paris. Claude Giessner-Prettre, Jacqueline Langlet, Hilaire Chevreau; Laboratoire de Chimie Théorique, Paris. Emmanuel Bertounesque, Caroline Courme, Jean-Claude Florent*; Institut Curie, Paris. Céline Roux, Johanna Foret, Laurent Salmon*, Clotilde Policar; ICMO, Orsay. David Perahia; Laboratoire d Ingéniérie des Protéines, Orsay. Rob J. Deeth University of Warwick, Royaume-Uni. Jens Antony; Freie Universitat Berlin. Morris Krauss*, Hillary Gilson; CARB, Rockville, MD, USA. G. Andrès Cisneros, Tom Darden*; NIEHS, Chapel Hill, NC, USA.

3 Requirements Separability Anisotropy Nonadditivity Cooperativity in multiply hydrogen-bonded complexes and anticooperativity in polycoordinated complexes of divalent cations. Transferability

4 Restricted Variational Space Analysis. Stevens, W. J., and Fink, W., Chem. Phys. Letts 1987, 139, 15

5 The SIBFA (Sum of Interactions Between Fragments Ab initio computed) procedure E is a sum of five separate contributions, each of which as a counterpart from ab initio quantum chemistry. 1. Electrostatic, E MTP, with distributed ab initio multipoles anisotropy 2. Short-range repulsion E rep, expressed as sums of bond-bond, bond-lone pair, and lone pair-lone pair interactions anisotropy 3. Polarization, E pol non-additivity and anisotropy 4. Charge-transfer, E ct non-additivity and anisotropy 5. Long-range dispersion, E disp

6 Recent refinements. -Inclusion of a penetration component E pen to the electrostatic multipolar contribution E MTP Piquemal, Gresh, Giessner-Prettre J. Phys. Chem. A., 2003, 107, Inclusion of a Ligand Field contribution for open-shell transition Metal cations Piquemal, Williams-Hubbard, Fey, Deeth, Gresh, Giessner-Prettre J. Comput. Chem., 2003, 24, 1963

7 Angular variations of E exch (RVS) and E rep (SIBFA) in formate-water complex (Piquemal et al., JCTC 2007, 3, 824) Energy (kcal/mol) Rotation angle H-CO (degres) Erep* Eexc HF classical Lennard- Jones

8 Stacked formamide dimer. Evolutions of first-order electrostatic and repulsion contributions upon rotation around the z axis (Piquemal et al., JCTC 2007, 3, 824). Stacking formamide dimer z=3.3 A 8 Electrostatic energy (kcal/m ol) Ec HF EMTP* classical EMTP -6 Rotation angle Stacked N-methylformamide dimer 10 8 Upon rotations around the z axis, the E MTP * curve is superimposed over the E c (ab initio) curve. E rep * recovers the angular features of E exch, while a 1/R 12 formula has a flat behaviour Energy (kcal/mol) Rotation angle(degrees) E rep * E éxc (RVS) Lennard Jones

9 Representation of two water clusters with n=16 and n=20 molecules water cluster (n=20) in a cubic ice structure; water cluster (n=16) extracted from a Monte-Carlo simulation

10 Interaction energies in water clusters (n=12-20) in energy-minimized cubic ice structures and (for n=16) as extracted from a Monte-Carlo simulation Number of water molecules (M-C) 20 RVS SIBFA* RVS SIBFA* RVS SIBFA RVS SIBFA E c /E MTP* E exch /E rep E E polrvs /E pol* E polkm /E pol E ct E

11 Interaction energies in water clusters (n=12-20) in energyminimized cubic ice structures and (for n=16) as extracted from a Monte-Carlo simulation Number of water molecules (M-C) 20 RVS SIBFA* RVS SIBFA* RVS SIBFA RVS SIBFA E c /E MTP* E exch /E rep E E polrvs /E pol* E polkm /E pol E ct E

12 Cu(II) polyligated complexes (Piquemal et al., JCC 2003, 24, 1963) Energy-minimized square planar complex: E(SIBFA = kcal/mol E(MP2) = kcal/mol Energy-minimized square planar complex: E(SIBFA) = kcal/mol E(MP2) = kcal/mol

13 Spontaneous assembly of double-stranded helicates from oligobipyridine ligands and Cu(I) cations: Structure of an inorganic double helix Lehn, J.-M., Rigault, A., Siegel, J., Harrowfield, J., Chevrier, B., Moras, D. Proc. Natl. Acad. Sci., 1987, 84, 2565

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15 X-ray-derived binuclear binding site of β-lactamase with OH(-) and H2O ligands. The Zn-Zn distance is 3.5 A Gresh et al, JCC, 2005, 26, 1113

16 Alternative binuclear binding site of β-lactamase with OH(-) and H2O ligands. The Zn-Zn distance is 4.3 A

17 Values of the Q-C and SIBFA interaction energies in the Zn(II) binuclear binding site of β-lactamase a)-c) Standard complexes in the fragilis binding site; d) Complex derived from HF energy minimization. a-c): Zn-Zn distances of 3.0, 3.5, and 3.8A, respectively. d): Zn-Zn distance of 4.8 A. a) b) c) d) RVS SIBFA RVS SIBFA RVS SIBFA RVS SIBFA E c /E MTP E exch /E rep E E pol (RVS)/E pol * E pol (HF)/E pol E ct E ct* E

18 Values of the Q-C and SIBFA interaction energies in the Zn(II) binuclear binding site of β-lactamase a)-c) Standard complexes in the fragilis binding site; d) Complex derived from HF energy minimization. a-c): Zn-Zn distances of 3.0, 3.5, and 3.8A, respectively. d): Zn-Zn distance of 4.8 A. a) b) c) d) RVS SIBFA RVS SIBFA RVS SIBFA RVS SIBFA E c /E MTP E exch /E rep E E pol (HF)/E pol E ct E ct* E

19 Values of correlated (DFT and MP2) interaction energies and of E tot (SIBFA) in the fo β-lactamase binding sites. a b c d E(DFT) a E tot (SIBFA) E(MP2) b a LACVP3** basis set; b CEP 4-31G(2d) basis set

20 D- and L- thiomandelate and D- and L- captopril

21 Monodentate complex d-ii of captopril with β-lactamase active site (Antony et al, JCC, 2005, 26, 1131)

22 Monodentate complex d-iii of captopril with β-lactamase

23 Bidentate complex d-iv of captopril with β-lactamase active site

24 Bidentate complex d-v of captopril with β-lactamase

25 Bidentate complex d-vi of captopril with β-lactamase

26 Monodentate complex l-i of L-captopril with β-lactamase

27 Bidentate complex l-v of L-captopril with β-lactamase

28 Bidentate complex l-vi of L-captopril with β-lactamase

29 Complex d-i of thiomandelate with β-lactamase binding site

30 Complex d-ii of thiomandelate with β-lactamase

31 Complex d-iii of thiomandelate with β-lactamase

32 Complex l-i of thiomandelate with β-lactamase

33 Complex l-iii of thiomandelate with β-lactamase

34 Thiomandelate and captopril complexes to b-lactamase binding site : SIBFA vs. HF interaction energies Thiomandelate Captopril d-i d-i a d-i b d-ii d-ii a d-ii b d-iii l-i l-ib l-ii l-iii d-i d-ii d-iii d- IV d-v d- VI l-i l-ii l-iii DE inter (kcal/mol) SIBFA HF (CEP 4-31G(2d)) HF (6-311G**)

35 Thiomandelate and captopril complexes with b-lactamase model binding site. Values of DE(SIBFA) with Edisp and correlaled quantum-chemical interaction energies DE inter(kcal/mol) Thiomandelate Captopril d-i d-i a d-i b d-ii d-ii a d-ii b d- III l-i l-ib l-ii l-iii d-i d-ii d- III d- IV d- V d- VI l-i l-v l-vi SIBFA MP2(CEP 4-31G(2d)) DFT(CEP 4-31G(2d)) DFT(6-311G**)

36 Design of novel inhibitors of Zinc Phosphomannose Isomerase. Céline Roux, Johanna Foret, Laurent Salmon Institut de Chimie Moléculaire et des Matériaux d Orsay, Orsay, France Jean-Philip Piquemal, Lalith E. Perera NIEHS, Research Triangle Park, North Carolina, USA Benoit de Courcy, Nohad Gresh IFR Biomédicale, Paris, France

37 Zn-dependent type I phosphomannoisomerase (PMI): catalyzes the isomerization of D-fructose 6-phosphate to D-mannose 6-phosphate. It is involved in: -illness of immuno-suppressed individuals; -opportunistic infections in patients with cystic fibrosis; -leishmaniasis.

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39 X-ray structure of Phosphomannoisomerase metalloenzyme

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48 Interaction energies (kcal/mol) of the bifunctional inhibitors 5PAH and 5PAA in the model binding site (MBS) of PMI (Roux et al., JCC 2007, 28, 938) PMI-5PAH a-b PMI-5PAA c-d PMI e A A' A'' B B' C C' D D' E a E b E(DFT) b a: CEP 4-31G(2d) basis set b: 6-311G** basis set

49 Interaction energies (kcal/mol) of the bifunctional inhibitors 5PAH and 5PAA in the model binding site (MBS) of PMI. PMI-5PAH a-b PMI-5PAA c-d PMI e A A' A'' B B' C C' D D' E a E E b E(DFT) b Εtot a: CEP 4-31G(2d) basis set b: 6-311G** basis set

50 Interaction energies (kcal/mol) of the bifunctional inhibitors 5PAH and 5PAA in the model binding site (MBS) of PMI A A' A'' B B' C C' D D' DE inter (kcal/mol) DE(SIBFA) HF CEP 4-31G(2d) HF LACVP3** DEtot(SIBFA) DFT LACVP3**

51 Compared evolutions of G solv (LC), E el (LC), G solv (PB) and E el (PB) in complexes A-D

52 The specificity of Acyl Transfer from 2- mercaptobenzamide thioester to the HIV-1 nucleocapsid protein Miller-Jenkins, L. et al., J. Am. Chem. Soc., submitted

53 A O O NH S CH 3 247: R 1 = NH 2 295: R 1 = OCH 3 O R 1 B K E G G C Zn N F K H * E G 40 H I G 45 Q 25 A C M K K * Zn K * N W D MQK * C C GNFRNQRKTVK RAPRK * C C KG TERQAN O RS C CH 3 Cys Cys Lys Zn His Cys O CH 3 C Cys Cys Lys Zn His Cys O CH 3 C Cys NH Lys Cys His Cys Zn COOH COOH COOH

54 Energy-minimized complex of 2-mercaptobenzamide thioester (TC4) to C-terminal Zn-finger of HIV-1 nucleocapsid protein

55 Interaction energies (kcal/mol) of TC4 with the Arg32- Asn55 Zn-finger of HIV-1 NCp7 E 1 a 19.4 a E pol a E ct E disp a E tor a 1.6 δe tot a δ G solv a δ E tot +δ G solv a: After subtraction of the energies of the Zn-finger and of TC4 separately minimized.

56 Extensions 1) Additional open-shell metal cations. 2) Interface to a molecular dynamics engine and Particle Mesh Ewald techniques. 3) Interface to a Monte-Carlo engine. 4) Extraction of multipoles and polarizabilities derived from correlated density matrices. 5) QM/MM.

57 Gaussian Electrostatic Model (GEM) JP Piquemal* and G. A. Cisneros* N. Gresh T. Darden Towards a third-generation force-field based on fitted densities (density fitting) follows the SIBFA energetic scheme up to CCSD

58 X-ray structure of isopentenyl diphosphate isomerase (Wouters et al., JBC 2003, 278, 11903

59 Acknowledgments Support by CNRS, la Ligue Nationale contre le Cancer, and generous access to the supercomputer Centers of CINES (Montpellier), IDRIS (Orsay) and CRIHAN (Rouen).