Population-based heteropolymer design to mimic protein mixtures
Open accessAbstract
Biological fluids, the most complex blends, have compositions that constantly vary and cannot be molecularly defined 1. Despite these uncertainties, proteins fluctuate, fold, function and evolve as programmed 2–4. We propose that in addition to the known monomeric sequence requirements, protein sequences encode multi-pair interactions at the segmental level to navigate random encounters 5,6; 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.
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Ideal random copolymerization of the six functional monomers has minimal composition drift during polymerization and enables statistically controlled sequences.
“Therefore, we aimed to statistically replicate the sequence features of functional classes through ideal random copolymerization of the six functional monomers, which has minimal composition drift during polymerization and enables statistically controlled sequences19,27–29.”
From Data-driven de novo design of super-adhesive hydrogels (2025) · cites this paper as [19]
The Design and synthesis of RHP ensembles section says the chains are statistically sequence-defined and were made using 2–4 of six selected monomers. The Methods section describes their polymerization, but neither passage establishes ideal random copolymerization or minimal composition drift during polymerization; the paper also does not say that all six monomers were copolymerized together. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIdeal random copolymerization of functional monomers (with near-unity reactivity ratios) plays an important role in achieving the statistical sequence features essential for mimicking protein functions.
“This finding underscores the important role of ideal random copolymerization of functional monomers (with near-unity reactivity ratios) in achieving the statistical sequence features essential for mimicking protein functions19,27.”
From Data-driven de novo design of super-adhesive hydrogels (2025) · cites this paper as [19]
The ‘Design and synthesis of RHP ensembles’ section describes statistically sequence-defined heteropolymers designed to match protein segmental features, and the concluding design discussion says segmental sequence information can guide statistical sequence control to replicate protein functions (page numbers unavailable). The paper uses experimentally determined monomer reactivity ratios to simulate sequences, but our copy does not say the ratios are near unity or that ideal random copolymerization is important to achieving those features. (LLM, conf=0.85)
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Data-driven de novo design of super-adhesive hydrogels
Liao, H., Hu, S., Yang, H., Wang, L., Tanaka, S., Takigawa, I., Li, W., Fan, H., & Gong, J. P. (2025) · Nature · doi:10.1038/s41586-025-09269-4 · Cited by 169 · see citing works
“This finding underscores the important role of ideal random copolymerization of functional monomers (with near-unity reactivity ratios) in achieving the statistical sequence features essential for mimicking protein functions 19,27 .”
- Authors
- Ruan, Z., Li, S., Grigoropoulos, A., Amiri, H., Hilburg, S. L., Chen, H., Jayapurna, I., Jiang, T., Gu, Z., Alexander-Katz, A., Bustamante, C., Huang, H., & Xu, T.
- Affiliations
- University of California, Berkeley (US)
- Massachusetts Institute of Technology (US)
- Xiamen University (CN)
- Northwestern University (US)
- Howard Hughes Medical Institute (US)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Xu, Ting
- ORCID
- Venue
- Nature
- Published
- 2023-03-08
- Volume
- 615
- Issue
- 7951
- Pages
- 251-258
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10468399
- OpenAlex
- W4323543021
- Cited by
- 64
- References
- 47
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 17 · 2023: 12
- FWCI
- 5.70
- Type
- journal article
- Language
- en
- Update notices
- correction (2023-08-30)
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Science Foundation (2104443, W911NF-13)
- U.S. Department of Defense
- U.S. Department of Energy (DE‐AC02‐06CH1135, -AC02-05CH11231, DE AC02 05CH11231, KC3104, DE-AC02-)
- Alfred P. Sloan Foundation (g-2021-16757)
- Eidgenössisches Nuklearsicherheitsinspektorat
- Defense Threat Reduction Agency (HDTRA11910011, HDTRA1)
- Office of Science (DE-AC02-06CH1135, DEAC02–05CH11231, DE-AC02)
- University of California, San Francisco
- Division of Materials Research
- Basic Energy Sciences (DE-AC02, DE-AC02-05CH11231., KC3104, AC02–05CH11231, DE-AC02-06CH1135)
- Army Research Office (W911NF- 13-1-0232, W911NF-13-1-, W911NF-13, W911NF)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Organic Chemistry › Advanced Polymer Synthesis and Characterization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- heteropolymers, protein mimicry, protein mixtures, biological fluids, protein folding, protein thermal stability, intermolecular interactions, protein libraries
- MeSH terms
- Amino Acid Sequence, Body Fluids, Cytosol, Polymers, Protein Conformation, Proteins, Serum Albumin, Bovine, Protein Folding, Biomimetics, Biomimetic Materials, Synthetic Biology
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