Toward Artificial Proteomes: Sustaining Life with Proteins Designed De Novo
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, our lab designs large libraries of novel proteins encoded by millions of synthetic genes. Many of these novel proteins fold into stable 3-dimensional structures (see graphic below), 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 living cells. In some cases, these novel proteins function in vivo 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 findings 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 from ‘scratch’ using non-natural sequences.
Link to a seminar Dr. Hecht presented at NASA: NAI Director’s Seminar: Michael Hecht
Image below shows a ribbon diagram of
the 3-dimensional structure of S-824, a protein designed in the Hecht lab