- Title
- Studies in computational biochemistry: Computer prediction of xenobiotic metabolism and the three-dimensional solution structure of residues 1-28 of the Alzheimer's disease amyloid beta-peptide
- Author
- Talafous, Joseph
- Degree
- Doctor of Philosophy, Case Western Reserve University,
Chemistry, 1995.
- Advisor
- Gilles Klopman
- Pages
- 229p.
- Abstract
- META is a new knowledge-based expert system that simulates the biotransformation and metabolism of xenobiotics. By application of a collection of rules which supply knowledge, the program recognizes key functional groups within the complete xenobiotic structure and substitutes them to predict possible metabolites. META employs established methodologies to predict lipophilicity, stability, and reactivity of the metabolites. A comprehensive knowledge base was constructed to model mammalian xenobiotic metabolism with META methodology by consulting experts in medicinal chemistry. Metabolic pathways are often experimentally observed to compete for substrates, which is modeled by the prioritization of the rules. The META-4 algorithm optimizes the prioritization knowledge base development. Another algorithm, called Graphsort, is used to assign a unique name to chemical entities that can be represented by graphs. Uniqueness is accomplished by canonical ordering of the nodes using novel node invariants based on distance distributions. The β-peptide is the major proteinaceous component of amyloid deposits in Alzheimer's disease. The three-dimensional solution structure of resid ues 1 to 28 of the amyloid β-peptide was determined using nuclear magnetic resonance spectroscopy, distance geometry, and molecular dynamics techniques. The nuclear magnetic resonance data used to derive the structure consisted of nuclear Overhauser enhancements, vicinal coupling constants, and temperature coefficients of the amide-NH chemical shifts. In membrane-like media, the peptide folds to form a predominately α-helical structure with a bend centered at residue 12. There is strong backbone homology with mellitin and alamethicin, which may provide a structure-based explanation to the β-peptide ion-channeling and aggregation properties. The side-chains of histidine-13 and lysine-16 reside on the same face of the α-helix and their proximity may constitute a binding site for the heparan sulfate proteoglycans. The molecular details of this structure could assist in the design of rational treatments to curtail the binding of heparan sulfate proteoglycans, or inhibit an α-helix → β-sheet conversion that may occur during the early stages of amyloid plaque formation in Alzheimer's disease.
- Keywords
- computational biochemistry Computer prediction xenobiotic metabolism three-dimensional solution structure residues 1-28 of the Alzheimer's disease amyloid beta-peptide
Document number: case1058197749.
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