Stability matters, too – the thermodynamics of amyloid fibril formation

Buell, Alexander K.

doi:10.1039/d1sc06782f

Cited by 56 publications

(51 citation statements)

References 139 publications

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“…It is also known that partially stable structures are many times involved in aggregation and in nucleation of amyloid fibrils formation. ,, Once initiated and formed, the aggregation process may persist for a long period of time given its unique kinetic stability. On the other hand, amino acid mutations, associated with aggregation growth, increase the population of partially unfolded and misfolded states by decreasing stability and cooperativity of the native state. − The thermodynamic stability is important to prevent promiscuous interactions . Following these arguments, it is possible that one of the reasons for the elimination of the aggregation process of Top7-2F5-biotin is the loss of the intermediate and partially folded state in the thermodynamic F ( Q ) profile upon biotinylation.…”

Section: Resultsmentioning

confidence: 99%

Biotinylation Eliminates the Intermediate State of Top7 Designed with an HIV-1 Epitope

Oliveira

2022

J. Phys. Chem. B

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Broadly neutralizing antibodies against HIV-1 are rare with the 2F5 antibody being one of the most protective. Insertion of an antibody epitope into a stable and small protein scaffold overcomes many of the obstacles found to produce antibodies. However, the design leads to grafting of epitopes that may cause protein aggregation. Here, I investigated the 2F5 epitope grafted into the Top7 as the scaffold in which the resulting immunoreactive protein precipitates along the storage time, as opposed to its completely soluble biotinylated version. Molecular dynamics showed that biotinylation eliminates the intermediate state of the scaffold-epitope Top7-2F5 by switching a noncooperative to a cooperative folding. The aggregation propensity of the Top7-designed proteins is examined in light of thermodynamic cooperativity and kinetic traps along the decreasing depth of the intermediate ensemble in the free energy landscape. This protocol may predict stable and soluble scaffold-epitopes with the purpose of composing novel therapeutic and diagnostic platforms.

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Section: Resultsmentioning

confidence: 99%

Biotinylation Eliminates the Intermediate State of Top7 Designed with an HIV-1 Epitope

Oliveira

2022

J. Phys. Chem. B

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“…The process of amyloid fibril formation is reversible, although the equilibrium monomer concentration is small for many proteins [ 48 ]. This concentration equals the thermodynamic equilibrium constant of fibril dissociation K F if only one form of the monomer is present and participates in aggregation.…”

Section: Kinetics and Thermodynamics Of Amyloid Fibril Formationmentioning

confidence: 99%

Molecular Mechanisms of Inhibition of Protein Amyloid Fibril Formation: Evidence and Perspectives Based on Kinetic Models

Sedov

Khaibrakhmanova

2022

IJMS

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Inhibition of fibril formation is considered a possible treatment strategy for amyloid-related diseases. Understanding the molecular nature of inhibitor action is crucial for the design of drug candidates. In the present review, we describe the common kinetic models of fibril formation and classify known inhibitors by the mechanism of their interactions with the aggregating protein and its oligomers. This mechanism determines the step or steps of the aggregation process that become inhibited and the observed changes in kinetics and equilibrium of fibril formation. The results of numerous studies indicate that possible approaches to antiamyloid inhibitor discovery include the search for the strong binders of protein monomers, cappers blocking the ends of the growing fibril, or the species absorbing on the surface of oligomers preventing nucleation. Strongly binding inhibitors stabilizing the native state can be promising for the structured proteins while designing the drug candidates targeting disordered proteins is challenging.

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“…Amyloids have since been recognized as a pathological conformation accessible to diverse proteins in many human diseases, including Alzheimer’s (AD) and Parkinson’s diseases [ 6 , 7 , 8 ]. However, several landmark experiments demonstrated that the amyloid state is not restricted to proteins involved in pathological conditions but can also be accessible to virtually any protein under the appropriate experimental conditions [ 6 , 8 , 9 , 10 , 11 , 12 ]. The resulting fibrils can in some cases lead to a novel pathological condition [ 13 ].…”

Section: The Amyloid Statementioning

confidence: 99%

Catalytically Active Amyloids as Future Bionanomaterials

Díaz-Espinoza

2022

Nanomaterials

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Peptides and proteins can aggregate into highly ordered and structured conformations called amyloids. These supramolecular structures generally have convergent features, such as the formation of intermolecular beta sheets, that lead to fibrillary architectures. The resulting fibrils have unique mechanical properties that can be exploited to develop novel nanomaterials. In recent years, sequences of small peptides have been rationally designed to self-assemble into amyloids that catalyze several chemical reactions. These amyloids exhibit reactive surfaces that can mimic the active sites of enzymes. In this review, I provide a state-of-the-art summary of the development of catalytically active amyloids. I will focus especially on catalytic activities mediated by hydrolysis, which are the most studied examples to date, as well as novel types of recently reported activities that promise to expand the possible repertoires. The combination of mechanical properties with catalytic activity in an amyloid scaffold has great potential for the development of future bionanomaterials aimed at specific applications.

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Stability matters, too – the thermodynamics of amyloid fibril formation

Abstract: Amyloid fibrils are supramolecular homopolymers of proteins that play important roles in biological function and disease. These objects have received an exponential increase in attention during the last decades, due...

Cited by 56 publications

References 139 publications

Biotinylation Eliminates the Intermediate State of Top7 Designed with an HIV-1 Epitope

Biotinylation Eliminates the Intermediate State of Top7 Designed with an HIV-1 Epitope

Molecular Mechanisms of Inhibition of Protein Amyloid Fibril Formation: Evidence and Perspectives Based on Kinetic Models

Catalytically Active Amyloids as Future Bionanomaterials

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