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The lactose repressor, LacI (I +  YQR ), is an archetypal transcription factor that has been a workhorse in many synthetic genetic networks. LacI represses gene expression (apo ligand) and is induced upon binding of the ligand isopropyl β-d-1-thiogalactopyranoside (IPTG). Recently, laboratory evolution was used to confer inverted function in the native LacI topology resulting in anti-LacI (antilac) function (I A  YQR ), where IPTG binding results in gene suppression. Here we engineered 46 antilacs with alternate DNA binding function (I A  ADR ). Phenotypically, I A  ADR transcription factors are the inverse of wild-type I +  YQR function and possess alternate DNA recognition (ADR). This collection of bespoke I A  ADR bind orthogonally to disparate non-natural operator DNA sequences and suppress gene expression in the presence of IPTG. This new class of I A  ADR gene regulators were designed modularly via the systematic pairing of nine alternate allosteric regulatory cores with six alternate DNA binding domains that interact with complementary synthetic operator DNA sequences. The 46 I A  ADR identified in this study are also orthogonal to the naturally occurring operator O 1 . Finally, a demonstration of full orthogonality was achieved via the construction of synthetic genetic toggle switches composed of two nonsynonymous unit pair operations that control two distinct fluorescent outputs. This new class of I A  ADR transcription factors will facilitate the expansion of the computational capacity of engineered gene circuits, via the scalable increase in the control over the number of gene outputs by way of the expansion of the number of unique transcription factors (or systems of transcription factors) that can simultaneously regulate one or more promoter(s).

Engineering a New Class of Anti-LacI Transcription Factors with Alternate DNA Recognition