Sequence and structure space model of protein divergence driven by point mutations

Author-Highlights
• A stochastic model of protein evolution in structure and sequence space is proposed.
• It uses real relationship between structure and sequence change.
• It reproduces cluster structure and sequence–structure divergence curve.
• It shows that point mutations alone can lead to the present protein diversity.

New folds of protein structures emerge in evolution as a result of insertions, deletions or shuffling of fragments of underlying gene sequences, and from aggregated effects of point mutations. The result of these evolutionary processes is a rich and complex universe of protein sequences and structures, with characteristic features such as heavy-tailed distribution of fold occurrences, and a distinct shape of relationship between sequence identity and structure similarity. Better understanding of how the protein universe evolved to its present form can be achieved by creating models of protein structure evolution. Here we introduce a stochastic model of evolution that involves residue substitutions as the sole source of structure innovation, and is nonetheless able to reproduce the diversity of the protein domains repertoire, its cluster structure with heavy-tailed distribution of family sizes, and presence of the twilight zone populated with remote homologs.