-cyclodextrin (BCD) host
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Structure and Internal Motion of Solvated beta-cyclodextrine. A Molecular Dynamics Study.
B. Manunza*1, S. Deiana1, M. Pintore1, and C. Gessa2
Keywords: cyclodextrine, polysaccharides, molecular dynamics
A 5 ns Molecular Dynamics simulation was performed on a system constituted by 512 water molecules and one b-cyclodextrin molecule in a cubic cell with 26 Å side. The internal motion of the solute molecule was investigated and compared with reports from Molecular Mechanics, Neutron scattering and Molecular Dynamics. The b-cyclodextrin structure is markedly distorted with the primary hydroxyl groups mostly pointing towards the inner cavity. The structure and the dynamics of water molecules in the first solvation shells were also investigated. An average number of 25 water molecules composes the inner shell forming a network of hydrogen bonds with the cyclodextrin hydroxyl groups.
Cyclodextrins are cyclic oligomers of 1->4 linked a-D-glucose monomers which form inclusion complexes with several molecules. Owing to this ability, cyclodextrins have been the subject of a considerable amount of studies in the past two decades [1-3]. Most of these studies focused on the inclusion complexes of cyclodextrins as well as on the use of these molecules as environment for chemical reactions [4-6]. More recently, these molecules have been employed in chromatography to separate constitutional isomers and enantiomers [7-8]. As a consequence, these molecules are of great interest to a wide range of scientists in most of the chemistry fields.
The structural features of cyclodextrins have also been investigated. Such studies mainly deal with the inclusion complexes in the solid state [9-11] or in solution phase [12].
In recent years several theoretical investigations have been reported [13-20] most of which focused on the inclusion process, whereas few concern the inherent structural features of cyclodextrins [13-14], none of these being performed on a fully solavated cyclodextrin structure.
In this paper we have applied the molecular dynamics to the study of b-cyclodextrin in water with the aim to test the ability of the commonly used force fields in describing the BCD-water interactions. We report here the results of a 5 ns MD simulation of a system constituted by a BCD molecule and 512 water molecules.
The -cyclodextrin (BCD) host
molecule is shown in Fig. 1.
Figure 1. The cyclodextrine molecule. Click on the image to retrieve a pdb file.
It consists of seven D-glucopyranose monomers connected by a-(1-4) linkages. Topologically this molecule can be represented by a toroid in which the primary and secondary hydroxyl groups are placed on the smallest and the largest circumferences, respectively (Scheme 1).
Scheme 1. Topology of the b-cyclodextrin ring.
No hydroxyl group is present within the toroid cavity which, accordingly, has a pronounced hydrophobic character. As a consequence, the ability of the BCD to form inclusion complexes in aqueous solution derives from its cavity, the interior of which is less polar than water.
The Molecular Dynamics (MD) experiments were performed employing the
DLPOLY2 [21]
program. The AMBER plus
GLYCAM [22]
force field was used with the necessary adaptations, while the BCD partial
atomic charges were calculated by the Gasteiger method [23]. In the simulation
all atoms and water molecules are free to move and all atoms are treated
explicitly. The starting -cyclodextrin
structure for the simulation was taken from the ‘BCDEX04’ entry of
the Cambridge Crystallographic Database. The DLPOLY utility wateradd
was employed to add 512 rigid Simple Point Charge ( SPC) [24] water molecules
in a cubic box with unit cell dimensions a=b=c=26.00 Å. Periodic
boundary conditions were adopted and a cut-off radius Rc=10 Å was
applied to the not bonded interactions; the Ewald summation method was
employed to evaluate the coulombic interactions with a dielectric constant
value of 1.0. The system was coupled to a thermal bath of T0=
298 K [25] using a temperature relaxation time of 0.1 ps. This value makes
the temperature coupling weak enough to avoid any significant effect on
the atomic properties of the system [14]. Calculations were carried out
on an IBM RS6000 and on CRAY T3D at CINECA
(Italy).
A 500 ps MD equilibration run on the BCD-water system was performed in the NPT (T= 298 K , P=1 atm) ensemble. The trajectory was then collected over the successive 2000 ps allowing the system to adjust its volume. The run was stopped after 2000 ps as no significant variation in the cell volume and in the Total Energy was observed during the last 1000 ps. The final cubic cell dimensions were a=b=c=25.45 Å. The endpoint of the NPT run was used as starting configuration for a 5000 ps trajectory in the NVT ensemble (T=298 K) which was recorded for the analysis.
A 30 ps movie of the internal motion in the BCD molecule was extracted from the trajectory and can be retrieved by clicking here; frames are spaced by 0.2 ps intervals. Snapshots from the movie are shown in Fig. 2.
Figure 2. Snaphots from the 30 ps movie of BCD internal motion. The hydrogen atoms and the water molecules are omitted for ease of view. Click on the images to retrieve the pdb files.
The BCD structure is strongly deformed and the primary hydroxyls are mostly rotated towards the interior of the cavity; this results in closing the bottom rim of the BCD molecule. Also, a network of interglucose primary OH bonds forms, accordingly to the radial distribution function shown in Fig. 3.
Figure 3. Radial Distribution Functions between the BCD hydrooxyl (OH) and glycosil (OS) oxygen atoms. In the equilibrium conformation the hydroxyl groups of the BCD molecule link together and with the glycosidic oxygens via the formation of hydrogen bonds, as evidenced by the first peaks of the g(r). The successive peaks reflects the periodicity of the BCD molecule.
This evidences the propensity for the primary hydroxyls to form small clusters maximising the hydrogen bonding cooperativity [26]. These findings well agree with the reports of a Molecular Mechanics investigation on symmetry breaking in cyclodextrins [13]. The mean distances between neighbouring glycosidic oxygen atoms (OS) calculated for the set of configurations in Fig. 2 are shown in Table 1 and indicate the extent of the deformation of the system. In the symmetric model the distances between the OS atoms (residues i to i+1 ) is about 4.5 Å and between residues i to i+2 is about 8.5 Å.
Table 1. Distances between the glycosidic oxygen atoms (OS) in residues i, i+1, and i+2.
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The cage of water molecules around the BCD is shown in Figs. 4-5. Only the water molecules within a radius of 3.5 Å from the BCD oxygen atoms are represented. Water molecules in the first solvation shells form a network of hydrogen bonds with both the primary and secondary hydroxyl groups.
Figure 4. Snapshot along the z-axis of the equilibrium conformation after 5 ns MD run. Only the water molecules whithin 3.5 Å from the BCD atoms are represented in spacefill model. Click inside the figure to retrieve the pdb file. The Water Oxygen and Hydrogen atoms are indicated as OW and HW, respectively, in all the .pdb files
Figure 5. Snapshot along the x-axis of the equilibrium conformation after 5 ns MD run. Only the water molecules within 3.5 Å from the BCD atoms are represented in spacefill model.Click inside the figure to retrieve the pdb file. The Water Oxygen and Hydrogen atoms are indicated as OW and HW, respectively, in all the .pdb files
The radial distribution function between the BCD hydroxyl oxygen atoms (OH) and the water oxygen atoms (OW)(Fig. 6) reveals the existence of two shells of water molecules around the BCD molecule at R= 3 and 5.4 Å respectively.
Figure 6. Radial Distribution Functions between the water oxygen atoms (OW) and the BCD hydroxyl (OH) and glycosidic (OS) oxygen atoms.
The gOW-OW function is almost equal to that computed for bulk water [27]. The BCD glycosidic oxygens (OS) interacts at a negligible extent with the water molecules. This is probably due to the repulsion of the hydrophobic carbon skeleton of the BCD ring.
The snapshots in Figs. 4 and 5 also show the existence of void spaces on the BCD surface corresponding to the hydrophobic carbon atoms of the BCD skeleton. This visual impression is confirmed by the examination of the radial distribution function between the water oxygens and the BCD carbon atoms in Fig. 7.
Figure 7. Radial Distribution Functions between the water oxygen atoms (OW) and the BCD carbon atoms (CT).
The plot evidences the hydrophobic effect of the inner cavity of the BCD molecule. The first shell of water molecules is 3.8 Å far from the BCD carbon atoms. The position of the first peak agrees with the report of about 3.6 Å for the methane-water system [28].
In order to better visualize the motion of the water molecules in the first solvation shell we realized a movie extracted from a 30 ps trajectory. Two version can be retrieved clicking here:
The frames are spaced by 0.1 ps steps
The water molecules move in prevalence onto the surface of the BCD molecule where they form a pattern corresponding to the BCD oxygen atoms. Only seldom one or two water molecules penetrate briefly into the cavity (Fig. 8).
Figure 8. Sections along the y-z and the x-y planes of the BCD-water complex. A couple of water molecules is enclosed in the cavity.Click inside the figure to retrieve the pdb file. The Water Oxygen and Hydrogen atoms are indicated as OW and HW, respectively, in all the .pdb files.
The fluctuations of the number of water molecules (NWM) in the first solvation shell is shown in Fig. 9. The data were collected at 0.1 ps regular steps from a 100 ps sample. The distribution of the NWM is shown in Fig. 10.
Figure 9. Fluctuation of the NWM over 1000 uniformly sampled configuration after 5ns MD run.
Fig. 10. Distribution of the NWM 000 uniformly sampled configuration after 5ns MD run.
Small fluctuation around the mean value of 25 water molecules occur within a time interval that can be roughly indicated in 25-30 ps.
An analysis of the BCD-water structure has been undertaken employing Molecular Dynamics and empirical force fields. Both inter- and intramolecular hydrogen bond networks have been highlighted thus agreeing with data from Molecular Mechanics [13], Molecular Dynamics [14,29], and Neutron/X-Ray diffraction[30-32] studies. Moreover, we wish to point out that the overall structure of the BCD molecule markedly differs from the highly symmetric ones usually reported in the literature. The BCD molecule spends most of its time in asymmetric conformations with the primary hydroxyl ring closed off. The results reported here validate the force field we employed and, in a future perspective, allow to undertake the investigation of the dynamics of a guest molecule inclusion in the presence of the solvent.
Thanks are due to CINECA (grant n. 95/565-5), MURST, and CNR for the financial support.