Position 289 and neighbouring residues are reasonably close to the de novo active site. However, the hotspot positions 280, 283 and 284 appear close to each other in a section of the a-helix that is removed from the Kemp elimination active site. Chemical shift perturbations (high Z scores) at these positions upon binding of a transition state analogue suggests, therefore, long-distance communication linked to catalysis. We will refer to positions 280, 283 and 284 collectively as the "a-set".