The substrate specificities of glutathione peroxidase (GPX)mimic, 6,60-ditellurobis(6-deoxy-b-cyclodextrin) (6-TeCD), for three hydroperoxides (ROOH), H2O2, tertbutyl hydroperoxide (t-BuOOH) and cumene hydroperoxide (CuOOH), are investigated through molecular dynamics (MD) simulations. The most stable conformations and the total interaction energies of complex of 6-TeCD with ROOH are used to evaluate the substrate specificity of 6-TeCD. The steady-state kinetics of 6-TeCD is studied and the Michaelis-Menten constant (Km) and second-order rate constant kmax/KROOH showthat 6-TeCDdisplays different affinity and specificity to ROOH. These results of experiments are well consistent with ones obtained by MD simulations, indicating that MD simulations could be applied to evaluation substrate specificity of small-molecule enzyme mimics.

Mouse CYP2C38 and CYP2C39 are two closely related enzymes with 91.8% sequence identity. But they exhibit different substrate binding features. In this study, three-dimensional models of CYP2C38 and CYP2C39 were constructed using X-ray crystal structure of human CYP2C8 as the template based on homology modeling methods and molecular dynamics simulations. Tolbutamide as the common substrate of CYP2C38 and CYP2C39 was docked into themand positioned in their active sites with different orientation. All-trans retinoic acid (atRA) is a specific substrate for CYP2C39 and not catalyzed by CYP2C38. By comparison of active site architectures between CYP2C38 and CYP2C39, the possible reasons affecting their substrate binding were proposed. In addition, Arg241, Glu300, Leu366 and Leu476 are identified as critical residue for substrates binding.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and one of the most common causes of dementia in the elderly. Acetylcholine esterase inhibitors (AChEI) are the main drugs used in the treatment of AD. In this work, docking studies have been performed in order to understand the in-teraction between a number of inhibitors (tacrine, rivastigmine, huperzine A, TV-3326 (ladostigil), donepezil and anseculin) and acetylcholine esterase (AChE). The calculated binding affinities between inhibitors and AChE increase in the order tacrine<rivastigmine<huperzine A<TV?3326 <donepezil<anseculin, which reflects the experimental inhibitory activity expressed in terms of the half maximal inhibitory concentration (the IC50 value). Of the above inhibitors, anseculin is the most useful drug for the treatment of dementia.

The unbinding process of three monosaccharides;galactose, glucose, and mannose;from human surfactant protein D (hSP-D) was investigated by the molecular docking and molecular dynamics methods to explore the cause of different dynamic interaction between these monosaccharides and the protein. The results show that the low affinity of galactose for hSP-D is attributed to the different binding conformation from the other two monosaccharides. The sugar coordinates to the calcium ion by the hydroxyl groups in the C2 and C3 atoms, so it cannot form the effective interaction with hSP-D. Glucose and mannose have similar binding conformations with hSP-D. Their difference in the affinity is induced by the interaction between the hydroxyl group in the C2 atom and the residue Asp325. The direction of the hydroxyl group in mannose results in the formation of the hydrogen bond with Asp325 and further makes mannose hydrogen-bond to the residues Glu329 and Arg343 by the hydroxyl groups in the C3, C4, and C6 atoms. As glucose only forms three hydrogen bonds with the residues Glu321, Asn323, and Glu329 by the hydroxyl groups in the C3 and C4 atoms, its interaction with hSP-D is weaker than that of mannose. Thus glucose has a lower energy barrier of dissociation. This work could provide the more penetrating understanding of hSP-D physiological functions.