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In summary, the data presented here indicate that protein robustness and adaptability can be explained through a model in which the main functional constraints are loaded in the sector¡ªa sparse, collectively evolving network within the protein structure. By saturation point mutagenesis, we find that sector positions selectively resist variation when challenged with wild-type ligand, but can flip to promote variation when challenged with a functionally distinct ligand. This epistatic coupling between ligand and sector underlies efficient functional adaptation, permitting considerable changes in specificity through very few mutations. Turned around, these data provide support for the hypothesis that the sector architecture might be the natural solution to design by evolution under conditions of constantly fluctuating environments. Such environments impose the need for maintaining robustness to mutation and adaptability to varying selection pressures and have been shown theoretically to influence the design of evolving systems. It will be important to now experimentally test the notion that the statistical history of fluctuations in conditions of selection fundamentally defines the physical design of natural proteins.

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