The simplicity of protein sequence-function relationships.

ABSTRACT: How complex are the rules by which a protein's sequence determines its function? High-order epistatic interactions among residues are thought to be pervasive, suggesting an idiosyncratic and unpredictable sequence-function relationship. But many prior studies may have overestimated epistasis, because they analyzed sequence-function relationships relative to a single reference sequence-which causes measurement noise and local idiosyncrasies to snowball into high-order epistasis-or they did not fully account for global nonlinearities. Here we present a reference-free method that jointly infers specific epistatic interactions and global nonlinearity using a bird's-eye view of sequence space. This technique yields the simplest explanation of sequence-function relationships and is more robust t

SUBMITTER: Park Y 

PROVIDER: S-EPMC11390738 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature