Chemical Evolution of Early Macromolecules: From Prebiotic Oligopeptides to Self‐Organizing Biosystems via Amyloid Formation

Abstract 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.