The Thermodynamics of Biomolecular CO 2 Capture: Disentangling Equilibria in Amino-Acid-based Systems

Abstract Amino acids and peptides are promising building blocks for aqueous biomolecular CO 2 capture systems, yet the coupled thermodynamics governing carbamate formation, proton transfer, carbonate speciation, and hydration remain difficult to resolve experimentally. Here, we establish isothermal titration calorimetry (ITC) as a quantitative platform for characterizing these coupled processes by integrating calorimetry with pH titrations, NMR spectroscopy, and a mechanistic thermodynamic model. Using L-lysine, L-arginine, and a series of Lys- and Arg-containing peptides, global fitting of ITC thermograms yielded thermodynamic parameters describing protonation and carbamate formation that accurately reproduced independent pH titrations and NMR-derived speciation. The analysis revealed that the characteristic biphasic calorimetric response originates from the coupled carbonate–amine equilibrium network and buffer collapse rather than carbamate saturation. Lys formed α-, ε-, and α,ε-dicarbamates and exhibited more favorable apparent carbamate thermodynamics than Arg with the ε-carbamate lying among the most favorable carbamate-forming amine sites reported for aqueous amines. Model-guided exploration of the fitted thermodynamic landscape further demonstrated that maximizing total CO 2 retention, amine-mediated capture, and carbamate formation are distinct optimization problems governed by different combinations of pH, temperature, and CO 2 loading. Extension to systematically spaced Lys-containing peptides showed that inter-amine separation alone does not control carbamate stability, highlighting the dominant role of the local thermodynamic environment in biomolecular CO 2 capture. This work establishes ITC as a powerful experimental approach for extracting CO 2 –amine thermodynamics and provides a predictive framework for the rational design and optimization of amino acid-, peptide-, and protein-based carbon capture systems.