Part I: Stucture and dynamics of beta-amyloid fibrils. Part II: Design of Taxol (Paclitaxel) analogs and predictive models; design of measles virus inhibitors; conformational analysis of alpha-helical mimics

For the past several decades, many scientists have put forth efforts to identify the structure of beta-Amyloid (Abeta). The resulting experimental evidence has led to several generalizations and contradictions as to the structural composition of amyloid fibrils. With few characteristics of Abeta being universally accepted, a recent experimentally defined model for the core residues of the Abeta peptide of Alzheimer's disease (AD), 10YEVHHQKLVFFAEDVGSNKGAIIGL35M, has emerged based upon solid-state NMR data, spectroscopic and scattering analyses. While these methods report on the average global structure of the fibril, benefiting immensely from the homogeneous assembly of Abeta(10--35), the energetic constraints that contribute to fibril dynamics and stability remain poorly understood. Here we investigate several models for amyloid fibril structure and exploit molecular dynamics simulations to extend the structural assignment of amyloid. Evidence is provided for a dynamic average ensemble, with transient backbone hydrogen bonds and internal solvation contributing to the inherent stability of Abeta fibrils. In fact, it may be the movement of these blocks of short stretches of hydrogen bonds that simultaneously permits global fibril stability and the local flexibility required to form long regular structures.