Key Assumptions
Phi value analysis fundamentally assumes a close relationship between structure and energy. If the energy landscape has a well-defined and relatively deep global minimum, the resemblance of a folding intermediate structure to the native state may closely correlate with the energy of that structure. However, if the energy landscape is relatively flat or has many local minima, the relationship may not hold strongly enough for free energy destabilizations to provide useful structural information. The method also assumes that the folding pathway is not significantly altered, although the folding energies may be. For nonconservative mutations this assumption might be fundamentally flawed; thus conservative substitutions are preferred, though they may yield smaller energetic destabilizations that are thus more difficult to detect experimentally. Lastly, the restriction of the phi value range as necessarily nonnegative assumes that the introduction of a mutation will not increase the stability and thus lower the energy of either the native or the transition state relative to those of the wild-type protein. Also, it is implicitly assumed that the interactions that stabilize a folding transition state are native-like in nature. Many recent studies of protein folding, however, have suggested that stabilizing non-native interactions in a folding transition state may aid in folding. An elegant example of this is given in Zarrine-Afsar et al. (2008) PNAS, where authors have demonstrated that stabilizing non-native interaction in the Fyn SH3 domain actually accelerated the folding rate of this protein.
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