Protein size and geometry govern mutational robustness

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.