Population-based heteropolymer design to mimic protein mixtures

Zhiyuan Ruan, Shuni Li, Alexandra Grigoropoulos, Hossein Amiri, Shayna L. Hilburg, Haotian Chen, Ivan Jayapurna, Tao Jiang, Zhaoyi Gu, Alfredo Alexander-Katz, Carlos Bustamante, Haiyan Huang and Ting Xu ()
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Zhiyuan Ruan: University of California Berkeley
Shuni Li: University of California Berkeley
Alexandra Grigoropoulos: University of California Berkeley
Hossein Amiri: University of California
Shayna L. Hilburg: Massachusetts Institute of Technology
Haotian Chen: University of California Berkeley
Ivan Jayapurna: University of California Berkeley
Tao Jiang: University of California Berkeley
Zhaoyi Gu: University of California Berkeley
Alfredo Alexander-Katz: Massachusetts Institute of Technology
Carlos Bustamante: University of California
Haiyan Huang: University of California Berkeley
Ting Xu: University of California Berkeley

Nature, 2023, vol. 615, issue 7951, 251-258

Abstract: Abstract Biological fluids, the most complex blends, have compositions that constantly vary and cannot be molecularly defined1. Despite these uncertainties, proteins fluctuate, fold, function and evolve as programmed2–4. We propose that in addition to the known monomeric sequence requirements, protein sequences encode multi-pair interactions at the segmental level to navigate random encounters5,6; 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.

Date: 2023
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DOI: 10.1038/s41586-022-05675-0

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