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hinge residues to be hypermutable. Also, the near neighbors of active site residues have
no particular reason to be conserved and thus their enrichment in hinges seems unlikely
to counter the tendency toward hypermutability.
This raises the question, why would residues that are functionally important not be
conserved? The answer may be that it is the intricate network of interactions within the
hydrophobic core of rigid regions on either side of the hinge that needs to be conserved,
and not the hinges themselves. The importance of the stability of these domains rather
than of any detailed properties of the hinges themselves is underscored by the significant
success of structure-based hinge predictors which analyze the interactions within the
domains and between the domains and the solvent, but which pay no particular attention
to the hinge region itself (Flores and Gerstein, submitted), or which implicitly or
explicitly find highly interconnected regions of the protein.
One might also ask, is it possible that co-evolution (alternatively called compensatory
mutation or mutational correlation) occurs in hinge residues even in the absence of
independent (single-site) conservation? Repeatedly investigators have found that co-
evolving residue pairs tend to be proximal in space and stabilize proteins, for instance by
periodically bridging consecutive turns of α-helices or by interacting across the contact
interface between two such helices. This is an active area of research with possible future
implications on hinge finding.
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