Design of protein-protein binding sites suggests a rationale for naturally occurring contact areas.

Molecular recognition is a critical process for many biological functions and consists in non-covalent 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 specification for molecular recognition is that the interaction must be selective, i.e. the host should strongly bind to one selected guest and poorly, if at all, to all other biomolecules. Our work focuses on the role played by the chemical heterogeneity and the steric compatibility on the selectivity 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 stabilise 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 ), 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 (Ka > 1040 l/mol) that what typically observed in natural biological processes. Conversely, the smallest surface tested is just the minimal size to allow for selective binding.