Computational Design of Ligand Binding Proteins

Fan Zheng, Gevorg Grigoryan

Barry L. Stoddard

Selective targeting of protein-protein interactions in the cell is of great interest in biological research. Computational structure-based design of peptides to bind protein interaction interfaces could provide a potential means of generating such reagents. However, to avoid perturbing off-target interactions, methods that explicitly account for interaction specificity are needed. Further, as peptides often retain considerable flexibility upon association, their binding reaction is computationally demanding to model-a stark limitation for structure-based design. Here we present a protocol for designing peptides that selectively target a given peptide-binding domain, relative to a pre-specified set of possibly related domains. We recently used the method to design peptides that discriminate with high selectivity between two closely related PDZ domains. The framework accounts for the flexibility of the peptide in the binding site, but is efficient enough to quickly analyze trade-offs between affinity and selectivity, enabling the identification of optimal peptides.