In a biological environment, the formation of a protein layer (protein corona) around nanoparticles immensely hampers its targeting capabilities and efficiency of specific delivery. Rational design of a nanoparticle remains one of the biggest challenges due to the lack of in-depth knowledge of the molecular mechanism of this corona formation on the different nanoparticle surfaces. Using computer simulation and experimental study, here, we establish for the first time the role of different surface properties like charge, chain length, architecture, and surface density of different surfactant molecules in the formation of the protein corona. We provide insights into the nanoparticle protein interaction, especially with respect to the structural orientation of a particular protein (human serum albumin) around a gold nanoparticle. We also derived the theoretical optimal conditions to avoid this corona formation. Such an efficient approach can pave the way to engineer smarter nanoparticles, which will avoid the protein absorption to keep their original properties unchanged.