Rotamer strain as a determinant of protein structural specificity

We present direct evidence for a change in protein structural specificity d ue to hydrophobic core packing. High resolution structural analysis of a de signed core variant of ubiquitin reveals that the protein is in slow exchan ge between two conformations. Examination of side-chain rotamers indicates that this dynamic response and the lower stability of the protein are coupl ed to greater strain and mobility in the core. The results suggest that man ipulating the level of side-chain strain may be one way of fine tuning the stability and specificity of proteins.