Protein size and geometry govern mutational robustness

Abstract

A fundamental question in structural biology centres around understanding protein evolution. Key to this process is mutational robustness, defined as the protein fold’s ability to absorb sequence changes without collapsing its structure. Here, we show that robustness is systematically shaped by simple features such as protein size, geometry, and oligomeric state. We used Foldseek-identified (structural) homologs to quantify family size across monomers and higher homo-oligomers. We found that proteins in larger families are consistently larger in size, more compact in atomic density, and less exposed to solvent. Strikingly, homo-oligomers occupy systematically larger families than monomers, revealing quaternary structure itself as a driver of mutational tolerance, not merely a functional supplement. This signature of robustness can be further linked to increasing functional complexity in proteins; those with adaptive, multifaceted biological roles belong to larger structural families than those with specific roles, thereby linking structural flexibility directly to evolutionary versatility. In short, simple yet overlooked features of protein geometry can explain mutational robustness and evolvability, offering a structural rationale for why certain protein families have diversified extensively while others remain in evolutionary stasis. eTOC blurb (short summary) Why do some protein folds diversify into thousands of variants while others remain rare and rigid? This work shows that the answer lies in geometry: proteins with denser cores, larger size, and higher-order oligomeric assembly tolerate mutations more readily, occupy larger structural families, and support more versatile biological roles. This reveals that protein size, shape, and self-assembly, not just sequence, are fundamental drivers of evolvability.