We present direct evidence for a change in protein
structural specificity due to hydrophobic core packing.
High resolution structural analysis of a designed core
variant of ubiquitin reveals that the protein is in slow
exchange between two conformations. Examination of side-chain
rotamers indicates that this dynamic response and the lower
stability of the protein are coupled to greater strain
and mobility in the core. The results suggest that manipulating
the level of side-chain strain may be one way of fine tuning
the stability and specificity of proteins.