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Molecular details of BSA adsorption on a silica surface are revealed by fully atomistic molecular dynamics (MD) simulations (with a 0.5 μs trajectory), supported by dynamic light scattering (DLS), zeta potential, multiparametric surface plasmon resonance (MP-SPR), and contact angle experiments. The experimental and theoretical methods complement one another and lead to a wider understanding of the mechanism of BSA adsorption across a range of pH 3-9. The MD results show how the negatively charged BSA at pH7 adsorbs to the negatively charged silica surface, and reveal a unique orientation with preserved secondary and tertiary structure. The experiments then show that the protein forms complete monolayers at ∼ pH6, just above the protein's isoelectric point (pH5.1). The surface contact angle is maximum when it is completely coated with protein, and the hydrophobicity of the surface is understood in terms of the simulated protein conformation. The adsorption behavior at higher pH > 6 is also consistently interpreted using the MD picture; both the contact angle and the adsorbed protein mass density decrease with increasing pH, in line with the increasing magnitude of negative charge on both the protein and the surface. At lower pH < 5 the protein starts to unfold, and the adsorbed mass dramatically decreases. The comprehensive picture that emerges for the formation of oriented protein films with preserved native conformation will help guide efforts to create functional films for new technologies.

The mechanism of hen egg white lysozyme (HEWL) adsorption on a negatively charged, hydrophilic surface has been studied using atomistic molecular dynamics (MD) simulation. Sixteen 90 ns trajectories provide adequate data to allow a detailed description of the adsorption process to be formulated. Two distinct adsorption sites have been identified. The main one is located on the N,C-terminal protein face and comprises Arg128 (the crucial one), supplemented by Arg125, Arg5, and Lys1; the minor one is used accidentally and contains only Arg68. Adsorption of this protein is driven by electrostatics, where the orientation of the protein dipole moment defines the direction of protein movement. The diffusion range on the surface depends on protein side-chain penetration through the surface water layers. This is facilitated by the long-range electric field of the charged surface, which can align polar side chains to be perpendicular to the surface. A simulation of adsorption onto a neutral ionic surface shows no such surface water layer penetration. Therefore, protein flexibility is seen to be an important factor, and to adsorb the HEWL has to adjust its structure. Nevertheless, at a flat surface only a slight loss of α-helical content is required. The adsorbed HEWL molecule is oriented between side-on and end-on ways, where the angle between the protein long axis (which mostly approximates the dipole moment) and the surface varies between 45° and 90°. Simulations with targeted mutations confirm the picture that emerges from these studies. The active site is located on the opposite face to the main adsorption site; hence, the activity of the immobilized HEWL should not be affected by the surface interactions. Our results provide a detailed insight into the adsorption mechanism and protein mobility at the surface. This knowledge will aid the proper interpretation of experimental results and the design of new experiments and functional systems.