Abstract <p>Mussel byssus is an established model for bioinspired design based on the discovery of 3,4-dihydroxyphenylalanine (DOPA)-mediated metal coordination cross-linking. Yet, synthetic mussel-inspired materials are inferior to native byssus. This stems from reductionist approaches in which the DOPA moiety is detached from its natural protein sequence and grafted onto polymers. Here, we investigated synthetic peptide derivatives of DOPA-rich protein mfp-1 to probe the role of amino acid sequence. Comparing the peptide to established mussel-inspired polethylene glycol (PEG)-DOPA polymers using spectroscopy and rheology, we found that peptide sequence strongly influences the pH at which DOPA-metal complexation forms, preference for specific metal ions (iron versus vanadium), and the mechanical properties of resulting materials. Moreover, we demonstrated that, mimicking natural assembly, mfp-1 peptides undergo sulfate-induced formation of fluid condensates that cross-linked preferentially with vanadium ions under acidic conditions relevant for native byssus formation. These findings provide new insights into byssus assembly and concepts for improved mussel-inspired materials.</p> Graphical abstract <p></p> Impact statement <p>Organisms such as spiders and mussels fabricate biopolymeric materials with properties that outperform those made by humans. For example, the sticky fibers comprising the mussel byssus are as tough as Kevlar, have self-healing properties, and can adhere to wet surfaces with ease—something that our best glues fail to do. Moreover, the byssus is produced under biologically and environmentally friendly conditions using biorenewable building blocks. Researchers have attempted to mimic these properties in synthetic materials over the last two decades by copying the characteristic DOPA-catechol chemistry discovered in the byssus. Yet, currently, these many thousands of mussel-inspired materials do not match the native properties. Here, we explored the hypothesis that this could stem from reductionistic synthetic approaches that remove the DOPA moieties from the biochemical context of the protein sequence in which they evolved. We test this hypothesis by investigating the metal-binding capacity, self-assembly behavior, and mechanical performance of synthetic peptides that mimic the full consensus sequence of a prominent byssus protein—mfp-1. Our findings indicate that removing DOPA from its evolved biochemical environment yields inferior performance and processability, helping explain common challenges with current mussel-inspired materials. This finding will inspire mussel-inspired materials with improved properties.</p>