Molecular recognition is a critical process for many biological functions and consists in noncovalent binding of different molecules, such as protein-protein, antigen-antibody, and many others. The host-guest molecules involved often show a shape complementarity, and one of the leading specifications for molecular recognition is that the interaction should ideally be specific, i.e. the host should strongly bind exclusively to one selected guest. Our work focuses on the role played by the chemical heterogeneity and the steric compatibility on the specificity power of the binding site between two proteins. We tackle the problem computationally, reducing the complexity of the system by simulating a protein and a surface-like element, that shapes part of the protein and represents the binding site of an interaction partner. We investigate four systems, differing in terms of binding site size. A significant result is that, despite the fact that protein and surface chemical sequences are interdependent and simultaneously generated to stabilize the bound folded structure, the protein is stable in the folded conformation even in the absence of the surface-like partner for all investigated systems. We observe that an increase of the surface area results in a significant increase of the binding affinity. Interestingly, our data suggest the presence of upper and lower limits for the maximum and minimum area size available for a binding site. Our data match the experimental observation of such limits (750-1500 Å2 ( Arkin and Wells Nat. Rev. Drug Discov. 2004 , 3 , 301 - 317 ) and provide a rationale for them: the extent of the binding site area is limited by the value of the binding constant. For large contact areas, at physiological conditions, the binding is orders of magnitude stronger ( K a > 1040 L/mol) than what is typically observed in natural biological processes. Conversely, the smallest surface tested is just the minimal size to allow for specific binding.