Consensus sequence design as a general strategy to create hyperstable, biologically active proteins

Abstract

Significance A major goal of protein design is to create proteins that have high stability and biological activity. Drawing on evolutionary information encoded within extant protein sequences, consensus sequence design has produced several successes in achieving this goal. Here, we explore the generality with which consensus design can be used to enhance protein stability and maintain biological activity. By designing and characterizing consensus sequences for six unrelated protein families, we find that consensus design shows high success rates in creating well-folded, hyperstable proteins that retain biological activities. Remarkably, many of these consensus proteins show higher stabilities than naturally occurring sequences of their respective protein families. Our study highlights the utility of consensus sequence design and informs the mechanisms by which it works.