Title:
Sustaining Life with Genes and Proteins Designed 'From Scratch'

Abstract:
A key goal of synthetic biology is to design novel proteins that fold and function in vivo. A particularly challenging objective would be to produce non-natural proteins that don't merely generate interesting phenotypes, but which actually provide essential functions necessary for the growth of cells. Successful design of such life-sustaining proteins would represent a step toward constructing "artificial proteomes" of non-natural sequences. In initial work toward this goal, we designed large libraries of novel proteins encoded by millions of synthetic genes. Many of these new proteins fold into stable 3-dimensional structures; and many bind biologically relevant metals, metabolites, and cofactors. Several of the novel proteins function in vivo providing essential activities necessary to sustain the growth of E. coli cells. In some cases, these novel proteins rewire gene regulation and alter the expression of endogenous genes. In other cases, the novel protein sustains cell growth by functioning as bona fide enzyme that catalyzes an essential biochemical reaction. These results suggest that (i) the molecular toolkit of life need not be limited to sequences that already exist in nature, and (ii) artificial genomes and proteomes might be built from non-natural sequences.