Population-based heteropolymer design to mimic protein mixtures

Biological fluids, the most complex blends, have compositions that
constantly vary and cannot be molecularly defined. Despite these
uncertainties, proteins fluctuate, fold, function and evolve as
programmed. We propose that in addition to the known monomeric sequence
requirements, protein sequences encode multi-pair interactions at the
segmental level to navigate random encounters; synthetic heteropolymers
capable of emulating such interactions can replicate how proteins behave
in biological fluids individually and collectively. Here, we extracted the
chemical characteristics and sequential arrangement along a protein chain
at the segmental level from natural protein libraries and used the
information to design heteropolymer ensembles as mixtures of disordered,
partially folded and folded proteins. For each heteropolymer ensemble, the
level of segmental similarity to that of natural proteins determines its
ability to replicate many functions of biological fluids including
assisting protein folding during translation, preserving the viability of
fetal bovine serum without refrigeration, enhancing the thermal stability
of proteins and behaving like synthetic cytosol under biologically
relevant conditions. Molecular studies further translated protein sequence
information at the segmental level into intermolecular interactions with a
defined range, degree of diversity and temporal and spatial availability.
This framework provides valuable guiding principles to synthetically
realize protein properties, engineer bio/abiotic hybrid materials and,
ultimately, realize matter-to-life transformations.