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Local elementary structures involve very few monomers. Consequently it is difficult to associate them to macroscopic measurable quantities and, in general, to detect them directly from experiment, except if their formation is associated with a local minimum of the overall energy (for example, "three-state folding"). On the other hand, the monomers participating in the formation of LES are among the strongest interacting amino acids. A possible way to learn about LES, is to perform protein engineering experiments (Refs. 31 and 45).
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The average is performed only over mutations which do not prevent folding.
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53
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6644228058
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note
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36 has a very low energy in the structure chosen as native. It is possible that nature selects less optimized sequences and that mutations in real proteins decrease folding time. In any case, the change in folding time associated with point mutations in hot sites (either positive or negative) is much larger than that associated with mutations in cold or warm sites.
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