The role of water in the primary nucleation of protein amyloid aggregation

• Published in: Biophysical chemistry Vol. 269; p. 106520
• Main Authors: Camino, José D., Gracia, Pablo, Cremades, Nunilo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-02-2021
• Subjects: Amyloid - chemistry; Amyloid - metabolism; Amyloid aggregation; Homogeneous nucleation; Humans; Hydrophobic and Hydrophilic Interactions; Intrinsically disordered proteins; Intrinsically Disordered Proteins - chemistry; Intrinsically Disordered Proteins - metabolism; Liquid-liquid phase separation; Primary nucleation; Protein Aggregates; Thermodynamics; Water - chemistry; Water activity; Primary nucleation; Liquid-liquid phase separation; Water activity; Homogeneous nucleation; Intrinsically disordered proteins; Amyloid aggregation
• ISSN: 0301-4622; 1873-4200; 1873-4200
• DOI: 10.1016/j.bpc.2020.106520

The understanding of the complex conformational landscape of amyloid aggregation and its modulation by relevant physicochemical and cellular factors is a prerequisite for elucidating some of the molecular basis of pathology in amyloid related diseases, and for developing and evaluating effective disease-specific therapeutics to reduce or eliminate the underlying sources of toxicity in these diseases. Interactions of proteins with solvating water have been long considered to be fundamental in mediating their function and folding; however, the relevance of water in the process of protein amyloid aggregation has been largely overlooked. Here, we provide a perspective on the role water plays in triggering primary amyloid nucleation of intrinsically disordered proteins (IDPs) based on recent experimental evidences. The initiation of amyloid aggregation likely results from the synergistic effect between both protein intermolecular interactions and the properties of the water hydration layer of the protein surface. While the self-assembly of both hydrophobic and hydrophilic IDPs would be thermodynamically favoured due to large water entropy contributions, large desolvation energy barriers are expected, particularly for the nucleation of hydrophilic IDPs. Under highly hydrating conditions, primary nucleation is slow, being facilitated by the presence of nucleation-active surfaces (heterogeneous nucleation). Under conditions of poor water activity, such as those found in the interior of protein droplets generated by liquid-liquid phase separation, however, the desolvation energy barrier is significantly reduced, and nucleation can occur very rapidly in the bulk of the solution (homogeneous nucleation), giving rise to structurally distinct amyloid polymorphs. Water, therefore, plays a key role in modulating the transition free energy of amyloid nucleation, thus governing the initiation of the process, and dictating the type of preferred primary nucleation and the type of amyloid polymorph generated, which could vary depending on the particular microenvironment that the protein molecules encounter in the cell.
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•Biological water plays multiple roles in amyloid aggregation.•The self-assembly of IDPs into amyloid structures can be thermodynamically driven by favourable water entropy contributions.•Large desolvation energy barriers prevent primary nucleation in the typical amyloidogenic IDPs under hydrating conditions.•Water strongly modulates the energy barrier for both heterogeneous and homogeneous amyloid nucleation.•Homogeneous nucleation is favoured under limited hydration conditions such as those found inside membrane-less organelles.