Preventing peptide and protein misbehavior.

Proteins provide remarkably diverse functionality in living systems by interacting and self-assembling together with other proteins into complexes, which represent key components of the nano-scale machinery of life (1). Such self-assembly processes generate intricate structures of considerable complexity that can perform a wide variety of functional roles, which range from generating motion to controlling transport across membranes. Where assembly processes are involved, there is, however, an inherent danger of misassembly, which can occur when a protein binds an incorrect partner or interacts with the appropriate partner in an incorrect manner. These types of aberrant behavior can lead to the formation of dysfunctional and even toxic molecular species. A particularly striking example of such misbehavior is the formation of amyloid fibrils (2), highly ordered elongated structures initially identified through their association with neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases (3, 4). This kind of pathological protein self-assembly is now known to occur in the context of more than 30 disorders, and the associated neurodegenerative diseases have been estimated to affect about 45 million people worldwide, a number that is expected to triple in the next 35 y as a consequence of the general increase in life expectancy in modern societies and the fact that aging is one of the key risk factors for this class of protein misfolding diseases (5). Hence, there is an urgent need for progresses in diagnosis and drug development against this class of disorders (6). A fundamental prerequisite to achieve these goals is a detailed understanding of the molecular mechanisms underlying the aberrant assembly of peptides and proteins, and how these mechanisms can be perturbed by the presence of other compounds. A crucial advance in this direction is presented in the PNAS report by Abelein et al. (7), which reveals the mechanism underlying the inhibition activity of the metal ion zinc against the aggregation of the amyloid β (Aβ) peptide, a peptide associated with Alzheimer’s disease. Understanding the molecular mechanisms underlying the misbehavior of peptides and proteins represents a great challenge. Indeed, the self-assembly of proteins into amyloid fibrils is a complex multistep process, which is driven by a range of microscopic reactions that are intricately connected, including nucleation events, which result in the formation of new aggregates, and growth processes, which lead to the increase in length of existing fibrils. A further complication of this picture is the fact that the nucleation processes can be facilitated through a positive-feedback mechanism by the presence of aggregates that have already been formed; this type of secondary nucleation was initially identified in the context of sickle hemoglobin aggregation (8), but has been now found to also play an essential role in the mechanism of amyloid formation for both major variants of the Aβ peptide (9, 10) as well for α-synuclein (11) and a peptide derived from the amyloidogenic protein islet amyloid polypeptide precursor (12). In light of this significant complexity at the molecular level, what is a fruitful way to make progresses in understanding the mechanisms of protein aggregation and develop strategies to prevent its occurrence? The International Union of Pure and Applied Chemistry definition of an “acceptable mechanism” for a chemical reaction states that it “must be consistent [...] with the [experimentally observed] rate law [...]” (13). Indeed chemical kinetics have been widely used in many areas of chemistry as a tool for obtaining mechanistic conclusions for small molecule reactions by connecting macroscopic observations and microscopic steps in a reaction. Therefore, a core strategy in the context of protein self-assembly consists of exploiting the knowledge of the kinetics of aggregation reactions, which can be experimentally obtained through macroscopic measurements, such as the acquisition of the time evolution of the aggregated material. However, the applicability of chemical kinetics to protein aggregation has been hampered for many years by the fact that “the rate law” for the complex reaction network underlying protein aggregation has been challenging to define based on molecular level events. Recent years, however, have seen a transformation both in the area of kinetic theory as well as in experimental methodology, and it is now becoming possible to use the full power of chemical kinetics to answer mechanistic questions for an increasing number of protein aggregation-related systems (9, 12, 14). A