Non-specific protein adsorption represents a significant challenge for the design of efficient and safe nanoparticles for biomedical applications since it may prevent functional ligands to target the desired specific receptors which can limit the efficacy of novel drug delivery systems and biosensors. The biofilm formation initiated by protein adsorption on surfaces limits the lifetime and safety of medical implants and tissue regenerative scaffolds. The development of biofouling resistant surfaces is therefore a major goal for the widespread uptake of nanomedicine. Here, we provide a relatively simple computational screening method based on the rational physically grounded criteria that may suffice in selection of surface grafted ligands for protein rejection, and test whether these criteria can be extrapolated from a specific protein to generic protein-resistant surfaces. Using all-atom molecular dynamics simulations we characterise four types of ligand functionalised surfaces at aqueous interfaces in terms of the surface hydrophobicity and ligand dynamics. We demonstrate how our hypothesised interfacial design based on the select physical characteristics of the ligated surfaces can enable the rejection of a protein from the surface. The ligand screening procedure and the detailed atomistic characterisation of the protein rejection process presented suggest that minimizing the adsorption of surface active proteins requires specific surface topographies and ligand chemistries that are able to maximise the entropic penalty associated with the restriction of the ligand dynamics and trapping interfacial water by adsorbed proteins.