Abstract
Living systems provide the most sophisticated materials known. These materials are created from a few dozen building blocks that are driven to self-organize by covalent and non-covalent interactions. Biology’s building blocks can be repurposed for the design of synthetic materials that life has not explored. In this Review, we examine the bottom-up design, discovery and evolution of self-assembling peptides by considering the entire supramolecular interaction space available to their constituent amino acids. Our approach focuses on sequence context, or how peptide sequence and environmental conditions collectively influence peptide self-assembly outcomes. We discuss examples of peptides that assemble through multimodal backbone, side chain and water interactions. We conclude that a more systematic (comparing sequences side-by-side), integrated (pairing computation and experiment) and holistic (considering peptide, solvent and environment) approach is required to better understand and fully exploit amino acids as a universal assembly code. This goal is particularly timely, because laboratory automation and artificial intelligence now have the potential to accelerate discoveries in these highly modular and complex materials, beyond the limited sequence space that biology uses.
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Fig. 1: Biology’s universal assembly code.
Fig. 2: Sequence determines the degree of order in peptide structures.
Fig. 3: Ordered systems.
Fig. 4: Disordered systems.
Fig. 5: Supramolecular dispersions.
Fig. 6: Environment-dependent assembly.
Fig. 7: Sequence evolution via dynamic combinatorial libraries.
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Authors and Affiliations
Nanoscience Initiative at Advanced Science Research Center of the Graduate Center of the City University of New York, New York, NY, USA
Kübra Kaygisiz, Deborah Sementa, Vignesh Athiyarath, Xi Chen & Rein V. Ulijn
Department of Chemical Engineering, The City College of New York, New York, NY, USA
Xi Chen
PhD Program in Chemistry, The Graduate Center of the City University of New York, New York, NY, USA
Xi Chen & Rein V. Ulijn
PhD Program in Physics, The Graduate Center of the City University of New York, New York, NY, USA
Xi Chen
Department of Chemistry, Hunter College, City University of New York, New York, NY, USA
Rein V. Ulijn
PhD Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY, USA
Rein V. Ulijn
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Kübra Kaygisiz
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2. Deborah Sementa
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3. Vignesh Athiyarath
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4. Xi Chen
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5. Rein V. Ulijn
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K.K., D.S., V.A. and R.V.U. did the literature research and wrote the original manuscript. K.K. and R.V.U. conceptualized the manuscript. X.C. and R.V.U. revised, supervised and provided the funding resources. The final manuscript was approved by all authors.
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Correspondence to Rein V. Ulijn.
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Glossary
Assembly dynamics
Rate of formation of a supramolecular structure, governed by interaction strength and range of involved intermolecular interaction types.
Environmental conditions
Factors such as pH, ionic strength, co-solutes, temperature and mechanical forces.
Exchange dynamics
Rate at which monomers in an assembled structure exchange with their environment, such as a solution.
Interassembly dynamics
Rate of interactions between assembled structures.
Internal dynamics
Reversible interactions between peptides that allow for rearrangement within an assembled structure.
Monomer dynamics
Flexibility of the peptide’s backbone to populate different dihedral angles.
Order and disorder
The regularity and irregularity of monomer arrangement in a self-assembled structure.
Out-of-equilibrium
A state in which a system is not in a thermodynamic equilibrium.
Pathway complexity
The variety of kinetic and out-of-equilibrium routes a monomer can take within a free-energy landscape to access different supramolecular morphologies.
Peptide sequence
The specific order and composition of amino acids in a peptide.
Polymorphism
The observation of multiple morphologies for the same type of molecule.
Sequence context
The combined influence of environmental conditions and sequence on the peptide self-assembly process and outcomes.
Supramolecular dynamics
The reversible changes in the structure of the assembly through movements and exchanges of monomers over time.
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Kaygisiz, K., Sementa, D., Athiyarath, V. et al. Context dependence in assembly code for supramolecular peptide materials and systems. Nat Rev Mater (2025). https://doi.org/10.1038/s41578-025-00782-6
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Accepted:31 January 2025
Published:13 March 2025
DOI:https://doi.org/10.1038/s41578-025-00782-6
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