Chemical Evolution of Early Macromolecules: From Prebiotic Oligopeptides to Self-Organizing Biosystems via Amyloid...

Short amyloidogenic oligopeptides (APRs) are proposed as early macromolecules capable of forming solvent-separated nanosystems under prebiotic conditions. This study provides experimental evidence that APRs, such as the aggregation-prone oligopeptide A (APR-A), can undergo mutational transitions to form distinct variants and convert to APR-B, either amyloid-like or water-soluble and non-aggregating. These transitions occur along a spectrum from strongly amyloidogenic (pro-amyloid) to weakly amyloidogenic (anti-amyloid), with the mutation sequence order playing a key role in determining their physicochemical properties. The pro-amyloid pathway facilitates heterogeneous phase separation, leading to amyloid-crystal formation with multiple polymorphs, including the first class 3 amyloid topology. By mapping these transitions, we demonstrate the potential co-evolution of water-soluble miniproteins and insoluble amyloids, both of which could have been pivotal in early bio-nanosystem formation. These insights into amyloid modulation provide a crucial step toward understanding amyloid control mechanisms.