Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying this deadly form of heart disease remain unclear. Although interstitial...

Amyloid formation occurs when normally soluble proteins and peptides misfold and aggregate into intractable threadlike structures called fibrils. There are currently more than 30 proteins associated with this aberrant structure, including the Aβ peptide in Alzheimer’s disease (AD) and transthyretin (TTR) in TTR amyloidosis. TTR is a homotetrameric transporter protein present in both cerebrospin...

Fibrin molecules polymerize to double-stranded fibrils by intermolecular end-to-middle domain pairing of complementary polymerization sites, accompanied by fibril branching to form a clot network. Mass/length measurements on scanning transmission electron microscopic images of fibrils comprising branch points showed two types of junctions. Tetramolecular junctions occur when two fibrils converg...

Assembly of normally soluble proteins into amyloid fibrils is a cause or associated symptom of numerous human disorders, including Alzheimer's and the prion diseases. We report molecular-level simulation of spontaneous fibril formation. Systems containing 12-96 model polyalanine peptides form fibrils at temperatures greater than a critical temperature that decreases with peptide concentration a...

In this paper, we study the stability of an initially straight elastic fibril clamped at one end, while the other end is subjected to a constant normal compressive force and a prescribed shear displacement. We found the buckling load of a sheared fibril to be always less than the Euler buckling load. Furthermore, if the end of the fibril loses adhesion, then the buckling load can be considerabl...

8. Electron microscopy provides evidence for an SA-tO-Sc transition in many other collagen fibrils (Stolinski & Breathnach, 1977; Lillie et al., 1977, and references therein). 9. An SA liquid-crystal model for the structure of the collagen fibril explains how hydroxyapatite crystals increase its Young’s modulus in bone (D. W. L. Hukins, unpublished work). The liquid-crystal properties of the co...

....................................................................................................................................1 1. Computational studies of protein folding and aggregation ..........................................3 1.1 Overview ....................................................................................................................3 1.2 Protein structure..........

A range of diseases is associated with amyloid fibril formation. Despite different proteins being responsible for each disease, all of them share similar features including beta-sheet-rich secondary structure and fibril-like protein aggregates. A number of proteins can form amyloid-like fibrils in vitro, resembling structural features of disease-related amyloids. Given these generic structural ...

We have investigated the self-assembly of fluorenylmethoxycarbonyl-conjugated dialanine (Fmoc-AA) molecules using combined computational and experimental approaches. Fmoc-AA gels were characterized using transmission electron microscopy (TEM), circular dichroism (CD), Fourier transform infrared (FTIR), and wide-angle X-ray scattering (WAXS). Computationally, we simulated the assembly of Fmoc-AA...