Inclusion Mechanism of Cyclodextrins with Glutathione†

doi:10.7503/cjcu20160375

Abstract

Abstract:

By using molecular dynamics simulations combined with free energy calculations, the inclusion modes of α-, β-, and γ-cyclodextrins(CDs) with glutathione(GSH) in an aqueous environment were investigated at the atomic level. The free-energy changes for the six possible inclusion processes of the three types of CDs with GSH were calculated. The results show that the inclusion complex formed by GSH and α-CD with the orientation that the glutamic acid(Glu) residue entering from the secondary rim of the CD is the most energetically favored, wherein the methylene chain of the Glu is completely buried in the cavity of α-CD, and three hydrogen bonds are formed between α-CD and GSH. It is worth noting that in this most stable complex structure, the sulfhydryl group of GSH is included at the secondary rim, thereby being protected by α-CD. Moreover, hydrophobic and hydrogen-bonding interactions constitute the main driving force responsible for the formation of the host-guest complex. The favorable inclusion mode of GSH with β-CD is similar to that with α-CD, but the corresponding complex of the former is less stable than that of the latter. On the contrary, for γ-CD, the favorable orientation is that the Glu residue enters the cavity from the primary side of the CD. From the free-energy calculations reported herein, the relative binding affinity with GSH follows the ranking order α-CD>β-CD>γ-CD.

Key words: Glutathione, Cyclodextrin, Molecular dynamics simulation, Free-energy calculation

CLC Number:

O641

TrendMD:

SHEN Wen, SHAO Xueguang, CAI Wensheng. Inclusion Mechanism of Cyclodextrins with Glutathione^†[J]. Chem. J. Chinese Universities, 2016, 37(10): 1809.

Figures/Tables 10

Fig.1 Initial structures of GSH(A) and α-CD(B)

Fig.2 Initial spacial arrangements of molecular systems with two orientations of GSH towards the CDs(A) Orien(Ⅰ); (B) Orien(Ⅱ). ξ: Projection onto the Z axis of the distance between the center of mass of Glu and that of CD.

Table 1 Summary of simulation systems with GSH and CDs

System	Method	Number of atoms	Time/ns
GSH: α-CD[Gly(Ⅰ)]^a	MD	7243	10
GSH: α-CD[Gly(Ⅱ)]^b	MD	7147	10
GSH: α-CD[Glu(Ⅰ)]^c	MD + ABF	7243	10+100
GSH: α-CD[Glu(Ⅱ)]^d	MD + ABF	7579	10+100
GSH: α-CD[Cys(Ⅰ)]^e	MD	7099	10
GSH: α-CD[Cys(Ⅱ)]^f	MD	7228	10
GSH: β-CD[Gly(Ⅰ)]^a	MD	7546	10
GSH: β-CD[Gly(Ⅱ)]^b	MD	7753	10
GSH: β-CD[Glu(Ⅰ)]^c	MD + ABF	7270	10+100
GSH: β-CD[Glu(Ⅱ)]^d	MD + ABF	7777	10+100
GSH: β-CD[Cys(Ⅰ)]^e	MD	7168	10
GSH: β-CD[Cys(Ⅱ)]^f	MD	7753	10
GSH: γ-CD[Gly(Ⅰ)]^a	MD	7450	10
GSH: γ-CD[Gly(Ⅱ)]^b	MD	8008	10
GSH: γ-CD[Glu(Ⅰ)]^c	MD + ABF	7450	10+100
GSH: γ-CD[Glu(Ⅱ)]^d	MD + ABF	8008	10+100
GSH: γ-CD[Cys(Ⅰ)]^e	MD	7783	10
GSH: γ-CD[Cys(Ⅱ)]^f	MD	7666	10

Fig.3 Distance between the center of residues of GSH and CD as a function of simulation time

Fig.4 Free-energy profiles for the inclusion of the Glu of GSH into CDs in two orientations(A) GSH:α-CD; (B) GSH:β-CD; (C) GSH:γ-CD. a. Orien(Ⅰ); b. Orien(Ⅱ).

Fig.5 Structures of the inclusion complexes of GSH with CD near the global minima of the PMFs in Fig.4(A1) GSH with α-CD, Orien(Ⅰ): ξ=-0.02 nm, d=0.05 nm, θ=14°; (A2) Orien(Ⅱ): ξ=-0.04 nm, d=0.22 nm, θ=12°; (B1) GSH with β-CD, Orien(Ⅰ): ξ=-0.30 nm, d=0.31 nm, θ=28°; (B2) Orien(Ⅱ): ξ=-0.18 nm, d=0.28 nm, θ=22°; (C1) GSH with γ-CD, Orien(Ⅰ): ξ=-0.10 nm, d=0.49 nm, θ=43°; (C2) Orien(Ⅱ): ξ=-0.05 nm, d=0.44 nm, θ=37°. ξ: Reaction coordinate in Fig.4; d: distance between the center of mass of Glu and the principal axis of CD; θ: angle between the side chain of Glu and the principal axis of CD.

Fig.6 Variation of average number of hydrogen bonds formed between GSH and α-CD as a function of the model reaction coordinate(A) and hydrogen bonds formed between GSH and α-CD(near the global minima of the PMF)(B)

Fig.7 Fluctuation of the area of the central plane formed by the six primary side carbon atoms(A) and the six glycosidic oxygen atoms(B) of the α-CD in the course of the threading process

Fig.8 Variation of the solvent-accessible surface area(SASA) for the hydrophobic chain of the Glu as a function of the model reaction coordinate

Fig.9 Structure of GSH-(A), free-energy profile for the inclusion of the Glu of GSH- into α-CD in Orien(I)(B) and structure of the inclusion complex of α-CD with GSH- near the global minima of the PMF(C)

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