Structure and dynamics of b-cyclodextrin and glycine at quantum mechanical level

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Structure and dynamics of
b-cyclodextrin and glycine at quantum mechanical
level
Theoretical Inorganic Chemistry Group
Hélio A. Duarte, Hélio F. Dos Santos, Thomas
Heine, Serguei Patchkovskii duarteh_at_ufmg.br Depart
ment of Chemistry - ICEx, Federal University of
Minas Gerais - UFMG
ACS 232nd National Meeting San Francisco, CA - USA
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Outline

• Motivation
• Spironolactone and its Complexes with
  b-cyclodextrin
• b-cyclodextrine in aqueous solution molecular
  dynamics using DFTB/MM approach.
• Glycine in aqueous solution molecular dynamics
  using full DFTB.

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b-cyclodextrine
Consists of 7 D-glucose linked by a (1-4)
interglucose bonds.
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b-Cyclodextrine

• Inclusion compounds
• Drug Delivery Systems
• Improved molecular switches
• Artificial enzymes
• Rotaxamers
• Nanoreactors
• Self-assembling systems

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Spironolactone and its Complexes with
b-cyclodextrin
Lula, Gomes, Piló-Veloso, De Noronha, Duarte,
Santos, Sinisterra, J. Inclusion Phenon. Macroc.
Chem., (2006).
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Spironolactone b-cyclodextrin

• Complexes 11 and 12 are formed and well
  characterized by ROESY-NMR.
• The rings A and DE are involved in the inclusion
  process.

Simulation at gas phase DC-SCC-DFTB
Zhechkov, L. Heine, T. Patchkovskii, S.
Seifert, G. Duarte, H. A. JCTC 2005, 1,
841. Elstner, et al., Phys. Rev. B, 1998, 58,
7260. Porezag, D. Frauenheim, T. Kohler, T.
Seifert, G. Kaschner, R. Physical Review B 1995,
51, 12947
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DC-SCC-DFTB calculations of 11 complexes at gas
phase
A-Head
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DC-SCC-DFTB calculations of 12 complexes at gas
phase
Head-Head arrangement.
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Inclusion process guesthost
according to Rekharsky and Inoue, Chem. Rev., 98,
1875.

1. penetration of the hydrophobic part of the guest
   molecule into the cylodextrin cavity
2. dehydration of the organic guest.
3. hydrogen bonding interactions
4. release of the water molecules to bulk water
5. conformational changes or strain release of the
   CyD upon complexation
6. how many water molecules are inside of the cavity
   before and after complexation.

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First step b-Cyclodextrine in solution
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b-cyclodextrine
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Methodology

• Born-Oppenheimer Molecular Dynamics
• QM/MM calculations
• QM DC-SCC-DFTB method
• MM employs Rappés universal force field (UFF).
• Cubic box with a lattice vector length of 34.92
  Å.
• 1385 water molecules and b-CyD.
• Microcanonical NVE ensemble.
• MD run 160 ps with a time step of 0.5 fs.
• Program deMon program (NRC-2004, Canada)

Zhechkov, L. et al. JCTC 2005, 1, 841.
Elstner, et al., Phys. Rev. B, 1998, 58,
7260. Porezag, D. et al. Physical Review B 1995,
51, 12947
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Setup of the simulation The periodic simulation
box is given. b-CyD, given in bold, is treated
quantum mechanically. The surrounding waters
(wireframe model) and all solute-solvent
interactions are approximated with the universal
force field (UFF) employing TIP3P partial charges
on water.
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Dihedral angles C2C3C4C5
O4O4O4O4 Angles C1O4C4
O4O4O4
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Structural parameters of the b-Cyclodextrine.
angles DC-SCC-DFTB DFT DC-SCC-DFTB-MD Exp.
C2C3C4C5 53?1 54?2 36?11 55?3
O4O4O4O4 -0.2?14 0?5 22?14 0.2?9
C1O4C4 123?17 116.9?0.9 114?3 118?1
O4O4O4 128?3 129?3 126?9 128?2
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• The root mean square deviations (RMSD) of the
  coordinates between two snapshots of a MD
  trajectory provides information about the
  flexibility of the b-CyD. The water surrounding
  the b-CyD acts as a cushion, decreasing its free
  motion.

Figure 2. RMSQ for b-CyD in gas phase (dashed)
and in solution (full).
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Figure 3. Configuration space taken by b-CyD in
aqueous solution.
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• In the radial distribution function (RDF), the
  range of r below 4.2 A corresponds to the
  encapsulated water molecules and integrates to
  7.9. This is in agreement with X-ray and neutron
  diffraction studies, which arrived at 7 water
  molecules.

Figure 4. RDF with respect to the distance
between the centres of mass of b-CyD and water
molecules.
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Motion of the water molecules in the cavity of
b-cyclodextrine. Solvent water molecules were
removed for better viewing.
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Figure 5. Configurational space taken by the
water molecules encapsulated in b-CyD. For sake
of clarity, only the initial structure of b-CyD
is shown.
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Table I. Average number and oxygen-oxygen
distance of hydrogen bonds between water and
?-CyD.
Biding site Average Number Average Number R(OO)(Å)
total in cavity
O2 and O3 1.51 ? 0.96 0.06 ? 0.21 3.18 ? 0.13
O4 0.77 ? 0.75 0.70 ? 0.72 3.32 ? 0.20
O5 0.91 ? 0.84 0.59 ? 0.73 3.25 ? 0.21
O6 1.36 ? 0.95 0.06 ? 0.23 3.16 ? 0.13
91 of the HBs formed with the glycosidic (O4)
and 64.8 of the pyranoid (O5) oxygens are due
to the encapsulated water molecules. For the
primary (O6) and secondary (O2,O3) hydroxyls, 96
of HBs are due to outer solvent.
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65
90
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Dwell time of water molecules in the cavity
A33.2A2

• No preferential side for the water molecules to
  enter the cavity.
• Roughly 50 of the water molecules come inside
  and get out through the top side.

A28.3A2
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Fig. 6. Dwell time distribution of the water
molecules.
There is strong peak at 70 fs dwell time of the
encapsulated water molecules. Much longer dwell
times are possible, up to several ps.
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Angiotensine(1-7)Cyclodextrine
Preliminary Results NOESY-NMR TYR (H3/H5 and
H2/H6) and b-CyD (H3 and H5)
The chemical structure of angiotensin (1-7),
AspArgValTyrIleHisPro
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Methodology

• Born-Oppenheimer Molecular Dynamics
• QM/MM calculations
• QM DC-DFTB method
• MM employs Rappés universal force field (UFF).
• Cubic box with a lattice vector length of 61.0 Å.
• 7381 water molecules and Ang(1-7)b-CyD.
• Microcanonical NVE ensemble.
• MD run with a time step of 0.5 fs.
• Program deMon program (NRC-2004, Canada)

Zhechkov, L. et al. JCTC 2005, 1, 841.
Elstner, et al., Phys. Rev. B, 1998, 58,
7260. Porezag, D. et al. Physical Review B 1995,
51, 12947
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Angiotensine(1-7)Cyclodextrine
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ANGCYD ? Preliminary Results
Structural parameters of the ang(1-7)b-CyD
angles b-CyD Ang(1-7)b-CyD
C2C3C4C5 36?11 44?11
O4O4O4O4 22?14 27?12
C1O4C4 114?3 115?4
O4O4O4 126?9 125?10
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Water are removed for better view.
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Glycine in Aqueous Solution
Progress report
Neutral form
Zwitterionic form
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Methodology

• Born-Oppenheimer Molecular Dynamics
• QM DC-DFTB method
• Cubic box with a lattice vector length of 16.0 Å.
• 129 water molecules and glycine.
• Microcanonical NVE ensemble.
• MD run 100 ps with a time step of 0.5 fs.
• Program deMon program (NRC-2004, Canada)

Zhechkov, L. et al. JCTC 2005, 1, 841.
Elstner, et al., Phys. Rev. B, 1998, 58,
7260. Porezag, D. et al. Physical Review B 1995,
51, 12947
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RDF with respect to the distance between the
centres of mass of glycine and water.
22 water molecules in the first solvation shell.
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Geometrical Properties of glycine
Angle PBE/TZVP DFTB DFTB-MD
Neutral form Neutral form Neutral form
5-4-2 113.2 114.3 114.3/-3.6
1-2-3 123.0 120.1 119.9/-2.8
3-2-4-5 -4.0 -13.2 78.9/-65.9
3-2-4-1 180.0 179.2 175.0/-3.8
Zwitterionic form Zwitterionic form Zwitterionic form
5-4-2 103.6 113.7 114.4 /- 3.5
1-2-3 132.4 119.3 119.2 /- 2.9
3-2-4-5 0.0 62.5 55.5 /- 55.0
3-2-4-1 180.0 178.8 174.8 /- 3.9
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Thermodynamical properties
Neutral ? Zwitterion
DFTB-MD DENVE -25.5 kcal/mol
PBE/TZVP/UAHF-PCM DG -23.4 kcal/mol Exp.
DH -10.3 kcal/mol DG -7.2
kcal/mol Quoted from Wada et al., Bull.
Chem.Soc. Jpn, 55, 3064 (1992).
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Grupo de Pesquisa em Química Inorgânica Teórica -
GPQIT

• Collaborators
• Prof. Ruben Sinisterra (DQ-UFMG)
• Prof. Hélio F. Dos Santos (DQ-UFJF)
• Prof. Gotthard Seifert (TU-Dresden)
• Prof. Thomas Heine (TU-Dresden)
• Dr. Serguei Patchkovskii (NRC-Canada)

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Grupo de Pesquisa em Química Inorgânica Teórica -
GPQIT

• Team
• Dr. Heitor Avelino de Abreu (CNPq)
• Antonio Noronha (PhD Student)
• Augusto Faria Oliveira (PhD Student)
• Luciana Guimarães (PhD Student)
• Guilherme Ferreira (IC)
• Conny Cerai (IC)
• Danniel Brandão (IC)
• Leonardo R. R. de Oliveira (IC)

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Support

• UFMG
• Instituto do Milênio Água - Uma Visão
  Mineral(PADCT/CNPq)
• CNPq
• CAPES
• FAPEMIG
• PRONEX

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