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Structure and dynamics of -cyclodextrin and glycine at

quantum mechanical level

Theoretical Inorganic Chemistry Group

Hélio A. Duarte, Hélio F. Dos Santos, Thomas Heine, Serguei Patchkovskii

duarteh@ufmg.brDepartment of Chemistry - ICEx,

Federal University of Minas Gerais - UFMG

ACS 232nd National MeetingSan Francisco, CA - USA

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Outline

• Motivation

• Spironolactone and its Complexes with -cyclodextrin

• -cyclodextrine in aqueous solution – molecular dynamics using DFTB/MM approach.

• Glycine in aqueous solution – molecular dynamics using full DFTB.

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-cyclodextrine

6.5 A

6.0A

7.9 A

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

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-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 -cyclodextrin

O

O

O

C H 3

H 3 C

1

3

2

4 5

6

7 8

9 1 0

1 1 1 2

1 3

1 4 1 5

1 6 1 7

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1 9

2 0

2 1

2 2

S

C H 3 O

2 3

2 4

A B

C D

E

(1)

Lula, Gomes, Piló-Veloso, De Noronha, Duarte, Santos, Sinisterra, J. Inclusion Phenon. Macroc. Chem., (2006).

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Spironolactone : -cyclodextrin

• Complexes 1:1 and 1:2 are formed and well characterized by ROESY-NMR.

• The rings A and DE are involved in the inclusion process.

*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

Simulation at gas phase:

DC-SCC-DFTB

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DC-SCC-DFTB calculations of 1:1 complexes at gas phase

A-Head

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DC-SCC-DFTB calculations of 1:2 complexes at gas phase

Head-Head arrangement.

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Inclusion process: guest:host

1. penetration of the hydrophobic part of the guest molecule into the cylodextrin cavity

2. dehydration of the organic guest.3. hydrogen bonding interactions4. release of the water molecules to bulk water5. conformational changes or strain release of

the CyD upon complexation6. how many water molecules are inside of the

cavity before and after complexation.

according to Rekharsky and Inoue, Chem. Rev., 98, 1875.

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First step: -Cyclodextrine in solution

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-cyclodextrine

6.5 A

6.0A

7.9 A

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-Born-Oppenheimer Molecular Dynamics

-QM/MM calculations

-QM : DC-SCC-DFTB* method

-MM: employs Rappé’s universal force field (UFF).

-Cubic box with a lattice vector length of 34.92 Å.

-1385 water molecules and -CyD.

-Microcanonical NVE ensemble.

-MD run: 160 ps with a time step of 0.5 fs.

-Program: deMon program (NRC-2004, Canada)

Methodology

*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. -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 O4O4’O4’’O4’’’

Angles: C1O4’C4’ O4O4’O4’’

O

O

HO

OH

OH

O

O

HO

HO

OH

O

O

HO

HOOH

O

O

HO

HO

HO

O

O

OHOH

HO

O

O

OH

OH

HO

O

O

OH

OH

OH 1

2

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56

5

1'2'

3'

4' 5'

6' 5'

4'

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angles DC-SCC-DFTB

DFT DC-SCC-DFTB-MD

Exp.

C2C3C4C5 531 542 3611 553

O4O4’O4’’O4’’’ -0.214 05 2214 0.29

C1O4’C4’ 12317 116.90.9

1143 1181

O4O4’O4’’ 1283 1293 1269 1282

Structural parameters of the -Cyclodextrine.

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2

,,

10k k

k C OC O

RMSD r t rN

• The root mean square deviations (RMSD) of the coordinates between two snapshots of a MD trajectory provides information about the flexibility of the -CyD. The water surrounding the -CyD acts as a cushion, decreasing its free motion.

Figure 2. RMSQ for -CyD in gas phase (dashed) and in solution (full).

0 10 20 30 40 500.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

<R

MS

D>

t

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Figure 3. Configuration space taken by -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 -CyD and

water molecules.

0 2 4 6 8 10 12 14 160.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

g cm

-cm

(r)

r

6.5

A

6.0A

8 A

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Motion of the water molecules in the cavity of -cyclodextrine.

Solvent water molecules were removed for better viewing.

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Figure 5. Configurational space taken by the water molecules

encapsulated in -CyD. For sake of clarity, only the initial

structure of -CyD is shown.

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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.

Biding site Average Number R(O…O)(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

Table I. Average number and oxygen-oxygen distance of hydrogen bonds between water and -CyD.

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90%

65%

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Dwell time of water molecules in the cavity

6.5 A

6.0A

7.9 A

A=33.2A2

A=28.3A2

•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.

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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

O

HO

O

NH2

NH

NHH2N

NH2

O NH

O

NH

OH

O

HN

O

NH

N

N

O

N

O

OH

The chemical structure of angiotensin (1-7), [AspArgValTyrIleHisPro]

Preliminary Results

NOESY-NMR

TYR (H3/H5 and H2/H6) and -CyD (H3 and H5)

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-Born-Oppenheimer Molecular Dynamics

-QM/MM calculations

-QM : DC-DFTB* method

-MM: employs Rappé’s universal force field (UFF).

-Cubic box with a lattice vector length of 61.0 Å.

-7381 water molecules and Ang(1-7):-CyD.

-Microcanonical NVE ensemble.

-MD run: with a time step of 0.5 fs.

-Program: deMon program (NRC-2004, Canada)

Methodology

*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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ANG:CYD → Preliminary Results

angles -CyD Ang(1-7):-CyD

C2C3C4C5 3611 4411

O4O4’O4’’O4’’’ 2214 2712

C1O4’C4’ 1143 1154

O4O4’O4’’ 1269 12510

Structural parameters of the ang(1-7):-CyD

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Water are removed for better view.

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Glycine in Aqueous Solution

Neutral form Zwitterionic form

Progress report

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-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)

Methodology

*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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Angle PBE/TZVP DFTB DFTB-MD

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

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

1

3

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Geometrical Properties of glycine

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Thermodynamical properties

Neutral Zwitterion

DFTB-MD: ENVE = -25.5 kcal/mol

PBE/TZVP/UAHF-PCM: G = -23.4 kcal/mol

Exp*. : H = -10.3 kcal/mol

G = -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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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)

Grupo de Pesquisa em Química Inorgânica Teórica - GPQIT

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

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