Amyloid-beta (Abeta) is a natively unfolded peptide found in all Alzheimer's disease patients as the major component of fibrillar plaques, which are recognized as an important pathological hallmark ...in Alzheimer's disease. The binding of copper to Abeta increases its neurotoxicity, as Cu2+ causes Abeta to become redox active and decreases the lag time associated with Abeta aggregation. In addition, the pH is a major factor that influences both the Abeta aggregation rates and Cu2+ binding. Hamiltonian replica exchange molecular dynamics (H-REMD) simulations enable atomistic insights into the effects of pH and Cu2+ complexation on the structure and dynamics of Abeta. To study the Abeta1-42/Cu2+ complex, we have developed new force-field parameters for the divalent copper ion ligated by the two histidine residues, His6 and His13, as well as the amine and carbonyl groups of Asp1, in a distorted square-planar geometry. Our comparative simulations reveal that both Cu2+ binding and a low pH-mimicking acidosis, linked to inflammatory processes invivo, accelerate the formation of beta-strands in Abeta1-42 and lead to the stabilization of salt bridges, previously shown to promote Abeta aggregation. The results suggest that Cu2+ binding and mild acidic conditions can shift the conformational equilibrium towards aggregation-prone conformers for the monomeric Abeta.
Alkaline sphingomyelinase, which is expressed in the human intestine and hydrolyses sphingomyelin, is a component of the plasma and the lysosomal membranes. Hydrolase of sphingomyelin generates ...ceramide, sphingosine, and sphingosine 1-phosphate that have regulatory effects on vital cellular functions such as proliferation, differentiation, and apoptosis. The enzyme belongs to the Nucleotide Pyrophosphatase/Phosphodiesterase family and it differs in structural similarity with acidic and neutral sphingomyelinase. In the present study we modeled alkaline sphingomyelinase using homology modeling based on the structure of Nucleotide Pyrophosphatase/Phosphodiesterase from Xanthomonas axonopodis with which it shares 34% identity. Homology modeling was performed using Modeller9v7. We found that Cys78 and Cys394 form a disulphide bond. Further analysis shows that Ser76 may be important for the function of this enzyme, which is supported by the findings of Wu et al. (2005), that S76F abolishes the activity completely. We found that the residues bound to Zn(2+) are conserved and geometrically similar with the template. Molecular Dynamics simulations were carried out for the modeled protein to observe the effect of Zinc metal ions. It was observed that the metal ion has little effect with regard to the stability but induces increased fluctuations in the protein. These analyses showed that Zinc ions play an important role in stabilizing the secondary structure and in maintaining the compactness of the active site.
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