Amyloid fibrillation has been intensively studied because of its association with various neurological disorders. While extensive time-dependent fibrillation experimental data are available and appear similar, few mechanistic models have been developed to unify those results. The aim of this work was to interpret these experimental results via a rigorous mathematical model that incorporates the physical chemistry of nucleation and fibril growth dynamics. A three-stage mechanism consisting of protein misfolding, nucleation, and fibril elongation is proposed and supported by the features of homogeneous fibrillation responses. Estimated by nonlinear least-squares algorithms, the rate constants for nucleation were approximately 10,000,000 times smaller than those for fibril growth. These results, coupled with the positive feedback characteristics of the elongation process, account for the typical sigmoidal behavior during fibrillation. In addition, experiments with different proteins, various initial concentrations, seeding versus nonseeding, and several agitation rates were analyzed with respect to fibrillation using our new model. The wide applicability of the model confirms that fibrillation kinetics may be fairly similar among amyloid proteins and for different environmental factors. Recommendations on further experiments and on the possible use of molecular simulations to determine the desired properties of potential fibrillation inhibitors are offered.

To help identify the etiological agents for amyloid-related diseases, attention is focused here on the fibrillar precursors, also called oligomers and protofibrils, and on modeling the reaction kinetics of the formation of the amyloid nucleus. Insulin is a favored model for amyloid formation, not only because amyloidosis can be a problem in diabetes, but also because aggregation and fibrillation causes problems during production, storage, and delivery. Small angle neutron scattering (SANS) is used to measure the temporal formation of insulin oligomers in H(2)O- and D(2)O-based solvents and obtain consistent evidence of the composition of the insulin nucleus that comprised three dimers or six monomers similar to that recently proposed in the literature. A simple molecular structural model that describes the growth of oligomers under a wide range of environmental conditions is proposed. The model first involves lengthening or end-on-end association of dimers to form three-dimer nuclei, and then exhibits broadening or side-on-side association of nuclei. Using different additives to demonstrate their influence on the kinetics of oligomer formation, we showed that, although the time required to form the nucleus was dependent on a specific system, they all followed a universal pathway for nucleus and precursor formation. The methods and analyses presented here provide the first experimental molecular size description of the details of amyloid nucleus formation and subsequent propagation to fibril precursors independent of kinetics.

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Lighting the way: Through the combination of a UV‐grafting process with the photoresponsive properties of spiropyran molecules, an optically reversible switching membrane surface was developed. This process can be used in preference to inducing physical movement of long‐chain SAMs toward an electrode and as a result improve many industrial opportunities including those dependent on surface wettability and molecular adhesion.

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