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,
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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 GreshLaboratoire de Pharmacochimie Moléculaire et Cellulaire
U648 INSERMUFR Biomédicale, Faculté de Médecine de Paris, France
Jean-Philip PiquemalLaboratoire de Chimie Théorique, Université Pierre-et-
Marie-Curie,
• 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.
Céline Roux, Johanna Foret, Laurent Salmon*, Clotilde Policar;ICMO, Orsay.
David Perahia;Laboratoire d’Ingéniérie des Protéines, Orsay.
Rob J. DeethUniversity 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.
• Separability
• Anisotropy
• Nonadditivity
– Cooperativity in multiply hydrogen-bonded complexes and anticooperativity in polycoordinated complexes of divalent cations.
• Transferability
Requirements
Restricted Variational Space Analysis.Stevens, W. J., and Fink, W., Chem. Phys. Letts
1987, 139, 15
The SIBFA (Sum of Interactions BetweenFragments 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, EMTP, with distributed ab initio multipolesanisotropy
2. Short-range repulsion Erep, expressed as sums of bond-bond, bond-lone pair, and lone pair-lone pair interactions
anisotropy3. Polarization, Epol
non-additivity and anisotropy4. Charge-transfer, Ect
non-additivity and anisotropy5. Long-range dispersion, Edisp
Recent refinements.
-Inclusion of a penetration component Epen to the electrostaticmultipolar contribution EMTPPiquemal, Gresh, Giessner-PrettreJ. Phys. Chem. A., 2003, 107, 10353
-Inclusion of a Ligand Field contribution for open-shell transitionMetal cationsPiquemal, Williams-Hubbard, Fey, Deeth, Gresh, Giessner-PrettreJ. Comput. Chem., 2003, 24, 1963
Angular variations of Eexch(RVS) and Erep(SIBFA) in formate-water complex (Piquemal et al., JCTC 2007, 3, 824)
9
10
11
12
13
14
15
16
125 145 165 185 205 225
Rotation angle H-CO (degres)
Ener
gy (k
cal/m
ol)
Erep*
Eexc HF
classical Lennard-Jones
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
-6
-4
-2
0
2
4
6
8
0 100 200 300 400
Rotation angle
Ele
ctro
stat
ic e
nerg
y (k
cal/m
ol)
Ec HF
EMTP*
classical EMTP
Stacked N-methylformamide dimer
Rotation angle(degrees)
0 50 100 150 200 250 300 350E
nerg
y (k
cal/m
ol)
0
2
4
6
8
10
Erep*Eéxc (RVS) Lennard Jones
Upon rotations around the z axis, the EMTP* curve is superimposed over the Ec(ab initio) curve. Erep* recovers the angular features of Eexch, while a 1/R12
formula has a flat behaviour
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
Interaction energies in water clusters (n=12-20) in energy-minimized cubic ice structures and (for n=16)
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
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
Alternative binuclear binding site of β-lactamase withOH(-) and H2O ligands. The Zn-Zn distance is 4.3 A
Values of the Q-C and SIBFA interaction energies in the Zn(II) binuclear binding site of β-lactamasea)-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
Values of the Q-C and SIBFA interaction energies in the Zn(II) binuclear binding site of β-lactamasea)-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
Interaction energies (kcal/mol) of the bifunctional inhibitors 5PAH and
5PAA in the model binding site (MBS) of PMI.
Compared evolutions of ∆Gsolv(LC), Eel(LC), ∆Gsolv(PB) and Eel(PB) in complexes A-D’
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
M Q K * G N F R N Q R K T V K R A P R K * K G T E R Q A NC
F
N
CG
K E GH
IAK
N
C CW
K *C
GK * E G
HQ
MK *
D
C
Z n Z n
1 5 1 0
1 5
2 0
2 5
3 0 3 5
4 0 4 5
5 0 5 5
B
A
2 9 5 : R 1 = O C H 3
2 4 7 : R 1 = N H 2S
N H
R 1
O
O
O
C H 3
C y s C y s
H is
C O O H
L y s
C y s
Z nC
O
C H 3
R S
C y s C y s
H is
C O O H
L y s
C y s
Z nCO
C H 3
C y s C y s
H is
C O O H
N H L y s
C y sCO
C H 3
Z n
Energy-minimized complex of 2-mercaptobenzamide thioester(TC4) to C-terminal Zn-finger of HIV-1 nucleocapsid protein
Interaction energies (kcal/mol) of TC4 with the Arg32-Asn55 Zn-finger of HIV-1 NCp7
E1a 19.4
Epola -15.7
Ecta -9.8
Edispa -41.7
Etora 1.6
δEtota -46.2
δ∆Gsolv
a +27.0 δ∆Etot +δ∆Gsolv -19.2
a: After subtraction of the energies of the Zn-finger and of TC4 separately minimized.
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.
Gaussian Electrostatic Model (GEM)
JP Piquemal* and G. A. Cisneros*N. GreshT. Darden
• Towards a third-generationforce-field
• based on fitted densities (density fitting)
• follows the SIBFA energetic scheme up to CCSD
X-ray structure of isopentenyl diphosphate isomerase(Wouters et al., JBC 2003, 278, 11903
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).