effects of methylation on zebularine studied by density functional theory lalitha selvam 1,...
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Effects of methylation on zebularine studied by density functional theory
Lalitha Selvam1, Vladislav Vasilyev2 and FengWang1
1Centre for Molecular Simulation, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia
2National Computational Infrastructure, Australian National University, Canberra, ACT 0200, Australia
June 22-26, 2009
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Outline
• Nucleoside analog - Zebularine • Molecular properties in position space - Geometry - Hirshfeld charges - Condensed Fukui analysis• Ionization spectra - Valence - Core• Momentum distribution• Summary• Acknowledgements
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Zebularine or zeb
• Chemically called as 1-β-D-ribofuranosyl-2-pyrimidone
• Cytidine analogue – lacks exocyclic amino group at C5 position
• Zeb - effective inhibitor of Cytidine deaminase and DNA methyltransferases
• Acts as an anti-tumor and anti-cancer drug
• Stability and Minimal toxicity -advantages of zebularine as drug
OH
O
OH
NN
O
OH
HH
OH
O
OH
NN
O
OH
HH
NH2
*Holy, A. et. al., Collect. Czech. Chem. Commun. 1985, 50, 393-417*Driscoll, J.S. et. al., J. Med. Chem. 1991, 34, 3280
cytidine
zeb
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Methylation of zebularine
Zebularine (zeb) 1-β-D-ribofuranosyl-5-methyl-2-pyrimidinone (d5)
C1’
C1’
C2’C3’
C4’
C5’
C6
C5C4
N3
C2
C7
C4
O5’
C5
C6
N3
C2N1
C5’ O4’
C4’
C3’ C2’
O5’
N1
Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)
O2
O2
O2’O3’O3’
O2’
O4’
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GeometryMolecular Properties Zeb d5
Eele + ZPE (Eh) -836.080026 -874.949037
R6(Å) 8.25 8.25
R5(Å) 7.49 7.49
N(1)-C(1’)(Å) 1.45 1.45
C(4)C(5)C(6) (◦) 114.61 116.24
O(5’)C(5’)C(4’) (◦) 111.06 111.23
C(6)N(1)C(2)N(3) (◦) 0.87 0.85
C(2)N(1)C(1’)C(2’) (◦) 114.85 117.05
N(1)C(1’)-O-C(4’) (◦) -160.81 -163.25
C(6)N(1)C(1’)C(2’) (◦) -66.04 -63.44
C(1’)C(2’)C(3’)C(4’) (◦) -30.2 -27.69
C(1’)OC(4’)C(3’) (◦) 17.33 21.58
µ (D) 6.81 6.75
OH
OH
O
OH
N
N
O
H3C
OH
OH
O
OH
N
N
O
1'2'
3' 4'
2'
3'
123
45
6
5'
2
7
41'
2'3' 4'
2'
3'
12
345
6
5'
4'
2
zeb d5
Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)
B3LYP/cc-pVTZ
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Conformation of sugar
Properties Zeb d5
χ -129.2 (anti) -127.37 (anti)
γ -65.81 -65.10
Pseudorotational angle,dP(deg)
137.07 (south) 131.23 (south)
Puckering amplitude,evmax(
◦)41.24 42.01
v0 -37.21 -39.78
v1 41.50 41.37
v2 -30.20 -27.69
v3 9.60 5.48
v4 17.33 21.58
Type PYR, C1’-exo PYR, C1’-exo
*Sun. G. et. al., J.Chem. Inf. Comput. Sci., 2004, 44, 1752-1762Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)
B3LYP/cc-pVTZ
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Hirshfeld charge*
LB94/et-pVQZ
rrr
rd)(
)(
)(ZQ molecule
epromolecul
AA
HirshfeldA
*Guerra, C. F. et. al., J Comp. Chem. 2004, 25, 189 Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)
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Condensed Fukui Function*
LB94/et-pVQZ *Saha, S. et. al., Mol. Simul. 2006, 32, 1261*Zhu, Q. et. al., J. Synchrotron Radiat. May 2009Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)
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Molecular Electrostatic potential (MEP)
projected on the base plane of C(5)-N(3)-N(1)
zeb d5
Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)
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MEP (contd.)
Cut through sugar plane of C(1’)-O(4’)-C(4’)
zeb d5
Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)
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Valence Ionization Potentials
Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)
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Valence spectra
SAOP/et-pVQZ calculation with an FWHM of 0.40 eV
Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)
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O-k and N-k spectra
LB94/et-pVQZ calculation with an FWHM of 0.40 eV
OH
OH
O
OH
N
N
O
H3C
OH
OH
O
OH
N
N
O
1'2'
3' 4'
2'
3'
123
45
6
5'
2
7
41'
2'3' 4'
2'
3'
12
345
6
5'
4'
2
zeb d5
Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)
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C-k spectra
OH
OH
O
OH
N
N
O
H3C
OH
OH
O
OH
N
N
O
1'2'
3' 4'
2'
3'
123
45
6
5'
2
7
41'
2'3' 4'
2'
3'
12
345
6
5'
4'
2
zeb d5
Selvam, L., Vasilyev, V. and Wang, F. J. Phys. Chem. B, May 2009 (Accepted)
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Momentum distribution (MD)
• MD – molecular orbital wavefunctions in momentum space
• Calculation of MD
• Provides qualitative structural information to understand chemical bonding
• Wavefunctions from both coordinate space and momentum space - to access information from both sides of the coin.
Experimental – Electron Momentum Spectroscopy (EMS)Theoretical – Fouriertransformation of coordinate space wavefunction
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MD
HOMO Total = Valence + core
Calculated using HEMS* code developed in Tsinghua university
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Summary• Zebularine and 1-β-D-ribofuranosyl- 5-methyl-2-
pyrimidinone – structurally differ in base composition
• Valence spectra clearly provides a scenario of methyl effect which is more significant in outer valence region than the inner valence
• MO’s 8, 18 and 37 – primarily dominant methyl related orbital
• Core shell spectra of O, N and C atoms differentiates the species locally with global red shifts in d5
• To understand the inter and intra molecular interactions and will be applied for other nucleosides analogues which are under study
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Acknowledgements
• Prof.Feng Wang (Supervisor)• Dr.Vladislav Vasilyev, ANU, Australia (3-D pdf)• Dr.Quan Zhu and Dr.Saumitra Saha for useful
discussions• Group members - Fangfang, Aravindhan, Anoja
and Yangyang
• Funding: Swinburne University of Techonology for SUPRA award
• National Computational Infrastructure (NCI) and Supercomputing facility at Swinburne for computing time
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Centre for Molecular SimulationSwinburne University of Techonology, Australia
http://www.ict.swin.edu.au/ictstaff/lselvam