COMPUTATIONAL DESIGN OF A SUBSTRATE-SPECIFICITY MUTANT OF A PROTEIN

The wild-type trp repressor of E. coli bound 5-methoxytryptophan a Trp analogue, less tightly than Trp, A mutant repressor (Val(58)-->Ala) t hat should bind 5-methoxytryptophan preferentially to Trp was computat ionally designed by free-energy calculations accompanied by free-energ y decomposition. The designed mutant was demonstrated by experiments t o bind 5-methoxytryptophan more tightly than Trp, consistent with the computational prediction, This success indicates the usefulness of fre e energy decomposition in protein design. (C) 1996 Wiley-Liss, Inc.