Sustainable carbon capture and greenhouse gas mitigation demand innovative strategies that harness biomolecular functions and integrate them into existing technologies. Enzyme-based systems offer a promising solution for sustainable CO₂ capture, yet their industrial adoption is limited by limited stability under harsh industrial conditions and the complexity of experimental optimization. Leveraging high-performance computing and large-scale molecular dynamics simulations, this study explores the design and behavior of biomimetic materials under diverse conditions, providing molecular insights to overcome these limitations. Carbonic anhydrase (CA), a ubiquitous metalloenzyme that efficiently converts CO₂ to bicarbonate—a fundamental physiological process in most living organisms—was selected as a model system for its remarkable catalytic performance and well-studied mechanism. Our sequence- and structure-based analyses uncovered critical factors such as pH, salt concentration, orientations and interactions of immobilized enzyme on surfaces. These insights, including the enzyme’s performance at variable pH, enabled the identification of strategies to improve catalytic efficiency and durability. By integrating these computational insights with experimental validation, this work establishes a foundation for robust, scalable CA-based systems for sustainable CO₂ capture, advancing global efforts to mitigate greenhouse gas emissions.