christian jelsch cnrs université de lorraine...crystallographic computing school rovinj croatia ecm...
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Laboratoire de Cristallographie & Résonance Magnétique
& Modélisations (CRM2) Nancy , France
Charge density refinement at ultra high resolution
with MoPro software
Crystallographic Computing School Rovinj Croatia ECM August 2015
Christian Jelsch
CNRS Université de Lorraine
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1) Crystallography at ultra high resolution
2) The MoPro software for electron density analysis
3) Derived Properties / Exemple of applications
4) Practical training on the software MoPro
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WHAT IS OBSERVABLE by X‐Ray CRISTALLOGRAPHY
HIGH X Y Zd 2 Å Thermal B factor isotropic
(Protein crystallography)
ATOMIC Thermal B anisotropic d 1 Å Hydrogen atoms
SUB-ATOMIC Deformation ofor Electron DensityULTRA HIGH
d 0.5 Å Atomic Charges
RESOLUTION
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Spherical Atom Model
Fourier Residual Electron Density: Fobs – Fcalc
2‐(indol‐3‐yl)‐1,1,3,3‐tetramethylthiouronium nitrate Lutz et al. Acta Cryst. (2008). C64,
Resolution 0.5 Å or sin/ = 1 Å‐1
Residual peakson covalent bonds
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Usual crystallography : spherical atoms
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atom (r) = core(r)
+
+
Hansen & Coppens (1978)
Acta Cryst. A34, 909
Multipolar Atom Model
Pval valence population
’
Plm multipoles
expansion/contraction
l '3 Rl (‘ r) m Plm Ylm
Pval 3 val (r)<1 >1
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Multipoles & Deformation Electron Density
C
OctupoleExample : sp2 Carbon atom
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3 dipoles 5 quadripolesZ
XY
7 octupoles
xyz(x2-y2)z
x[4z2‐(x2+y2)] y[4z2‐(x2+y2)]x(x2‐3y2) y(y2‐3x2)
2z3 -3z(x2+y2)
Multipoles
Local axessystem
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Deformation of Electron Density
∆ = molecule - isolated atoms
multipolar neutral & spherical
+/-0.05 e-/Å3
O
O H
Static :computed foratoms at rest
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The MoPro software for
electron density analysis
2)
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Subatomic Resolution Structure & Electron Density
~0.5Å
MOPRO Crystallographic
Refinement Software
Jelsch et al. J. Appl. Cryst. (2005) 38, 38‐54
Guillot Acta Cryst A. (2012). A68, s204.
Small Compounds & Biological Macromolecules
Atomic Resolution Structure with Hydrogen Atoms
0.7 – 1.4 Å Transfer Electron Density Databank
Developped at CRM2 laboratory, Nancy, Lorraine University
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RESTRAINTS :
introduce
additionnal information
into the system
Program MoPro Minimizes
E = H wH ( Hcalc - H
obs )2
+ r [( Rcalc - Rtarget ) /r ] 2
H=(h,k,l) reflection
intensity R restraints
Rtarget
r
Rcalc
LEAST SQUARES MINIMIZATION
Erestrain
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Some RESTRAINTS/ CONSTRAINTS in MoPro
Similar Valence Populations
Similar Multipoles
Similar Expansion/ Contraction coef
P Ptarget
Distance
Angle
Planarity
Similar Distances D1 D2
Similar Angles A1 A2
P = Ptarget
R/C
R/C
R/C
R
R
R/C
R/C
R/C
Stereo‐chemistry
Chargedensity
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Database of Multipolar Atoms
Database of Multipolar Atoms
Experimental Charge Density
of Small Compounds Crystals
Experimental Charge Density
of Small Compounds Crystals
PROTEINS or SMALL COMPOUNDS
at lower Resolution
PROTEINS or SMALL COMPOUNDS
at lower Resolution
TRANSFER
Compute Molecular Properties
Compute Molecular Properties
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Derived Properties
Exemple of applications
3)
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Electrostatic Potential derived from
the Multipolar Atom Model
V(r) = qi / ri + (r) / ri d3r
(r)deformationdensityaccumulation/depletion
Color surface according to V(r)+ / ‐
FidarestatInhitor of proteinaldose reductase
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Electrostatic Interaction Energy between dimers in the crystal packing
Closest interacting atoms
Bouhmaida et al.Acta Cryst B2009
Paracetamol
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Topological Analysis
Surfacenn
S
S
0)().( rr
Atomic Basins: (Atoms In Molecules ;Richard Bader )
Integrated
Property :
atomic charges
Total electron density
Gradient lines of
2 =
2/x2
+ 2/y2
+ 2/z2
Negative Laplacianin red :Electron accumulation
2 < 0
Laplacian
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Permits to caracterize nature & force of interactions (hydrogen bonds)
ji
ij xxrH
2 Diagonalization of Hessian matrix:
Ellipticity of a covalent bond : bonding
Places where the gradient of total electron density is zero
Topological Analysis : Critical Points
CP
Saddle CP
Bond paths
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*
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Practical presentation of
the software MoPro5)
MoProSuite Molecular Viewer & GUI
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MoProSuite Software components
MoProGUI general Graphical User Interface
Import2MoPro read .cif .pdb .xyz .res files
MoPro Crystallographic refinements
VMoPro Calculation of Molecular Properties
(density, potential, Laplacian..)
MoProViewer Molecular Viewer & GUI
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MoProGUI menu
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MoProGUI / MoPro Main Menus.
File declarations
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MoProViewer developed by Benoît Guillot, University Lorraine
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MoProViewer : a recent functionnality
Automatic calculation of Hirshfeld surfaceof a molecule In its crystal packing
Coloring according to interior or exterior atom types
Statistical analysis of crystal contacts cf Jelsch et al. IUCrJ (2014). 1, 119–128
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* Multipoles beyond hexadecapoles L=5 & L=6
* Several Kappa2 parameters for an atom (each multipole level)
* Enhanced rigid-bond restraints (Thorn, Dittrich & Sheldrick, 2012, Acta Cryst A)
* Eigenvalue filtering [ Radek Kaminski, Warsaw ]
* Block diagonal refinement
RECENT extensions/improvements in MoPro