Biological systems rely on intricate macromolecular machines that appear exquisitely fine-tuned for their functions. However, their origin through the process of evolution implies some degree of internal plasticity, allowing components to diversify, recombine, and adapt without catastrophic loss of function. Here, we set out to systematically interrogate modularity within an essential bacteriophage macromolecular machine—the DNA clamp loader (CL) complex—across three nested hierarchies of genetic organization: (1) the domain level, by transplanting AAA+ domains within one CL subunit from 72 diverse phage genomes; (2) the gene level, by combinatorially shuffling the three subunit-encoding genes between eight genomes; and (3) the complex level, by replacing the entire clamp loader with its orthologous counterparts. Our results reveal that functional modularity does not hold at the domain level but is nearly fully intact at the gene and full complex level even with significant sequence divergence. The data suggest that despite collective biochemical properties and extensive well-packed structural interfaces, biological macromolecular machines can nevertheless maintain weak or degenerate couplings between internal components, a property that may enhance their ability to adapt and diversify through evolution.
Vissamsetti et al. (Sun,) studied this question.