The amyloid-[beta] (A[beta]) peptide, a major component of the insoluble plaques associated with Alzheimer’s disease (AD), is the cleavage product of the transmembrane (TM) amyloid precursor protein (APP) and is known to possess amiphiphilic nature. To better understand the aggregation propensity and the role of peptide-membrane interactions in AD, knowledge about how small molecule and membrane characteristics affect binding, solvation, and secondary structure of A[beta]. Two site mutants, Ab(25-40) G37A and I32A, have been designed to interrupt the peptide backbone hydrogen bonding as well as reduce hydrophobic interactions. Further Thioflavin T (ThT) assays and circular dichroism (CD) results indicate that the hydrophobic interactions may be crucial in A[beta](25-40)’s intrinsic aggregation propensity and also play an important role in the interaction of between myricetin and A[beta]. Deep-ultraviolet resonance Raman (dUVRR) and size exclusion chromatography (SEC) experiments suggest that the various initial oligomeric state may contributes to the altered A[beta](25-40) property. Ab(25-40) is also found to spontaneously associate with anionic lipid bilayers and the structure of the membrane associated Ab(25-40) was depend on both the hydrophobic thickness of the bilayer and duration of incubation. Further studies regarding the full lengths peptide indicates similarity between Ab(25-40) and Ab(1-40). After spontaneously associating with negatively charged lipid bilayer, the full length Ab(1-40) initially adopts a mixed confirmation of [alpha]-helical and disordered structures. The mixed structures, then convert to a more b-sheet structures over longer timeframes, compared to the initial stage. b-sheet structure appears prior to the unwinding of [alpha]-helix, implying a progress in which b-sheet structure, formed initially from disordered regions, destabilized membrane solvated helical structure and then lead to the escape of peptide from the membrane surfaces. In order to better define dUVRR characteristics of membrane associated/solvated protein secondary structure and establish potential quantitative relationships between the spectral response and the size of protein TM domain, a series of model peptides, poly-(LA)x, were designed based on known TM helical peptide. It is found that both the length of the TM region of the peptide and the hydrophobic thicknesses determined by the lipid bilayer play important roles in the confirmation of the final adopted structure, while the overall peptide secondary structures are predictable based on the TM region/ hydrophobic thicknesses ratio and lipid bilayer composition.