Our recent work (CEA biology / physics DSV/DSM collaboration) within the CEA Toxicology Program have led to the development of an original methodology allowing a better understanding of protein adsorption on silica nanoparticles. The principle lies in identifying by proteomics analyses adsorbed and non-adsorbed proteins after contact of a sulfur-35 labeled protein extract with nanoparticles. The number of proteins found in the adsorbed and non-adsorbed groups was sufficient (>30 in both cases) to 1) perform a statistical comparative analysis allowing identification of physical-chemical determinants of adsorption / non-adsorption ; 2) perform molecular dynamics simulations to assess flexibility of proteins in both groups. This approach combining physical-chemical and structural properties in both groups was then validated with commercial SiO2 nanoparticles. Our analysis shows the importance of arginine residues in adsorption, in agreement with an electrostatic mechanism of adsorption. Furthermore, the high content inaromatic residues in non-adsorbed proteins was directly correlated to their strong structuration due to numerous π-π interactions.