Paired Fraction Electrochemical Programming of Peptide Reactions: An Integrative Theory for Ex Situ Control of Ligation, Enzymatic Bond Formation, and Oxidative Folding
Year: 2026
Type: preprint
Abstract: Electrochemical peptide technologies usually place a substrate, mediator, enzyme, or protected growing chain in direct electrical communication with an electrode. This Perspective proposes a different architecture: paired-fraction electrochemical programming, in which anodic and cathodic liquids are generated in a divided cell, chemically characterized, and then delivered independently to an electrode-free peptide reactor. The theory does not invoke persistent water memory and does not treat oxidation-reduction potential as a mechanism. Its physical basis is the transfer of measurable acid-base, redox, gas, and impurity capacities whose magnitude depends on charge, current efficiency, electrolyte composition, cell design, and time after generation. Six literature-identical propositions anchor the framework: Faradaic proportionality, complementarity of separated electrode compartments, protonation-controlled peptide reactivity, electrochemical controllability of peptide transformations, stage-dependent redox requirements, and sequence-specific susceptibility. The authorial contribution is the integration of these propositions into a closed-loop process based on fraction characterization, state-dose calculation, sequential addition, molecular feedback, and chemically matched controls. Three applications are developed: native chemical ligation followed by controlled oxidative folding; enzyme-catalysed peptide ligation or macrocyclization with dynamic control of the synthesis-to-hydrolysis balance; and post-synthetic redox maturation of disulfide-rich peptides. The framework predicts that benefit, if present, will be largest in multistage processes with opposing requirements and will disappear when a chemically prepared control reproduces all active species and trajectories. A falsification-oriented experimental programme is defined to distinguish a useful electrochemical generator from a non-specific pH adjustment and from unsupported claims of unique water states. The theory therefore provides a mechanistically bounded research agenda rather than evidence of manufacturing performance or pharmaceutical stability. Article type: Perspective and testable hypothesis. No experimental peptide-yield, stability, manufacturing-performance, or clinical data are reported.
Author: Kan, Ilyan
Institution: University of Toronto
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221759282
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