Toward artificial proteomes: Sustaining life with proteins designed de novo

Speaker: Professor Michael Hecht, Department of Chemistry, Princeton University

Host: Professor Jakob Winther, Biomolecular Sciences

Abstract
One of the key goals 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 living cells. Successful design of such life-sustaining proteins would represent a first 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 novel 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 function by providing catalytic activities, while in other cases, the non-natural protein sustains growth by providing novel regulatory functions that alter the expression of endogenous genes. These results suggest that (i) the molecular toolkit for life need not be limited to proteins that already exist in nature, and (ii) artificial genomes and proteomes might be built from non-natural sequences.