Mapping the Free Energy Landscape of Protein Adsorption at Solid-Liquid Interfaces

Abstract Protein adsorption at solid–liquid interfaces plays a crucial role in many biological and technological processes, including the design of biomaterials, biosensor performance, and biocatalysis. Understanding how proteins interact with surfaces is essential for controlling biofouling, optimizing medical implants, and engineering functional interfaces. Despite its significance, predicting adsorption behavior from molecular-level interactions remains challenging. In this work, we performed molecular dynamics simulations using umbrella sampling to sample the two-dimensional free-energy surface of bovine serum albumin adsorption on the anionic adsorbent Q Sepharose FF. By combining molecular dynamics simulations with enhanced free energy sampling techniques, we systematically explored the orientations and positions of the protein near the surface. No conformational changes were observed within the examined time scales. We obtained a comprehensive free-energy map that captures the adsorption behavior across the entire protein surface. This approach provides access to the adsorption free energy while accounting for contributions from all possible adsorption sites and orientations. The resulting landscape offers a detailed molecular-level understanding of how proteins interact with surfaces.