Metastability of Native Proteins and the Phenomenon of Amyloid Formation

Abstract

An experimental determination of the thermodynamic stabilities of a series of amyloid fibrils reveals that this structural form is likely to be the most stable one that protein molecules can adopt even under physiological conditions. This result challenges the conventional assumption that functional forms of proteins correspond to the global minima in their free energy surfaces and suggests that living systems are conformationally as well as chemically metastable.

Rational disruption of the oligomerization of the mini‐ferritin E. coli DPS through protein‐protein interface mutation

“…An alternative, and it should be noted, equally speculative, explanation would involve pointing out that through mutation, we may not only be altering the ground state energetics but the energies of transition states as well, which would surely affect the metastability of the oligomerized state opening up irreversibility which manifests as aggregation. 37 Our mutants may be useful tools to understand these mechanisms and states. In addition, as our stated long-term goal is to convert a mini-ferritin-forming monomer into one that assembles into a maxiferritin, and vice versa, this research where we have learned how to logically disassemble a miniferritin into an intermediate that may be common to both types of cages would be a reasonable initial step.…”

Kinetic theory of amyloid fibril templating

“…While these parameters were obtained in a carbohydrate system, the overall binding strength is comparable to that found in amyloids 38 and the explicit enthalpy and entropy contributions will permit the exploration of temperature effects. I take N β = 21 as suggested by Jiménez et al 28 and use the total number of amino acids on both peptide strands for the length L = 51.…”

“…Insulin is somewhat challenging to model because of the unknown fibril structure and the conformational constraints imposed by the disulfide bonds. Also, while the stability of insulin fibrils is known 38 this value is a combination of both intermolecular bonds and intramolecular contacts between the two peptide strands. Rather than attempt a blind deconvolution of these factors in the absence of a structure, I will neglect the attractive contribution from sidechain packing interactions and the repulsive contribution from conformational entropy and assume that the intermolecular H-bonds have the same thermodynamic properties as the bonds studied in detail by Ross and Rekharsky,39 …”

Alzheimer’s disease: addressing a twenty-first century plague

“…The fact that the cross-b structure is a characteristic arrangement of polypeptide chains is supported by the results of computer simulations (Auer et al 2008), as well as by theoretical analysis and by the results of investigations of the role of the arrays of hydrogen bonds that are features of this molecular architecture (Knowles et al 2007). Although the specific protein sequence does not itself define this overall architecture, it does play a major role in defining the relative propensity of a given protein to convert from its normal functional state to the polymeric amyloid state, a feature that turns out to be crucial in enabling proteins in living systems to avoid rapid conversion into their amyloid states that in many cases may be thermodynamically the most stable state of a protein molecule (Baldwin et al 2011). …”

“…One of the key advances in our understanding of Alzheimer's disease and related conditions has been the realisation that for many proteins, particularly those that are relatively small or have been fragmented by proteolytic enzymes, the amyloid state can be more stable thermodynamically than the native state even under physiological conditions (Baldwin et al 2011). The reason for the ability of such species to resist the conversion from their soluble forms into the amyloid state is, therefore, strongly dependent on the kinetics of this transition, the details of which are now beginning to emerge.…”