Distinct Functional Phases in Proteins: A Test by Large-Scale Protein Design




Subramanian, Subramanian Kanagarajan

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The biological properties of proteins - folding, biochemical functions, and evolvability - originate from the global pattern of interactions between amino acids. Coevolution studies suggest a model for this pattern in which the essential constraints are loaded in sparse networks of cooperative residues (termed sectors), embedded within an environment of weakly coupled residues. Here, we test this biphasic model for proteins using a protein design approach in the SHO1-mediated yeast osmo-sensing pathway. We computationally designed libraries of synthetic SHO1 SH3 domains in which the hierarchy of coevolution that defines sectors and their environment is gradually varied. We tested the designed sequences in a quantitative high-throughput assay for SHO1 function in vivo. The data show that sector amino acids contribute in an all-or-nothing fashion while surrounding amino acids have a more graded, near-independent contribution to function. These results support the biphasic model for the information content of protein sequences.

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