期刊
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
卷 70, 期 3, 页码 915-924出版社
WILEY
DOI: 10.1002/prot.21620
关键词
free energy nonadditivity; double mutant cycle; protein structure; cooperativity; network rigidity
资金
- NIGMS NIH HHS [R01 GM073082-01A1, R01 GM073082] Funding Source: Medline
Additivity principles in chemistry, biochemistry, and biophysics have been used extensively for decades. Nevertheless, it is well known that additivity frequently breaks down in complex biomacromolecules. Nonadditivity within protein double mutant free energy cycles of spatially close residue pairs is a generally well-understood phenomenon, whereas a robust description Of nonadditivity extending over large distances remains to be developed. Here, we test the hypothesis that the mutational effects tend to be nonadditive if two structurally well-separated mutated residues belong to the same rigid cluster within the wild type protein, and additive if they are located within different clusters. We find the hypothesis to be statistically significant with P-values that range from 10(-5) to 10(-6). To the best of our knowledge, this result represents the first demonstration of a statistically significant preponderance for nonadditivity over long distances. These findings provide new insight into the origins of long-range nonadditivity in double mutant cycles, which complements the conventional wisdom that nonadditivity arises in double mutations involving contacting residues. Consequently, these results should have far-reaching implications for a proper understanding of protein stability, structure/function analyses, and protein design.
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