Designing Selective Protein Binding Sites

Abstract

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 main specification for molecular recognition is that the interaction must be selective, i.e. the host should bind strongly 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 developed a computational design procedure, based on the caterpillar coarse-grained model, for a reference system where we fashioned the protein binding site as a protein-like surface which perfectly shapes a portion of the partner protein. The investigated range of surface area for the artificial binding sites falls in typical natural sizes (750 −1500 Å2). On the protein-like surface, we decorated anchoring points whose chemical functionalization is chosen so to optimise the binding with the protein. Using highly-efficient Monte Carlo simulations methods we explore the binding and folding properties of our artificial proteins. 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 protein-like partner for all investigated systems. Moreover, we observe that an increase of the surface area results in a decrease of specificity for the binding, therefore imposing an upper limit for molecular recognition binding sites at the typical physiological temperature range.