Curiously, our KIN analysis is based on Class A β-lactamases more broadly, i.e. the interaction network was evolutionarily optimized for the natural not de novo activity, and yet we show (Figure ) that the KIN scores nevertheless successfully discriminates between catalytically productive and non-productive sets of hotspots predicted from the NMR (residues from the β-set, which was successfully targeted for optimization, have low KIN evolutionary conservation scores, and conversely, residues from the poorly performing α-set have non-negligible KIN scores).