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"Whatever their evolutionary origin, our work demonstrates that energetically similar, nonfunctional conformations constrain the evolution of protein sequences. Proteins exist as ensembles of structures, with some highly populated and others rarely seen (54–57). The same mutation can have different effects on different structures within this energetic ensemble, redistributing their relative populations (54, 55, 58). This means that proteins must not only avoid mutations that destabilize native structures but also avoid mutations that stabilize nonnative structures."
