Computational Design of Peptides with Improved Recognition of the Focal Adhesion Kinase FAT Domain

We describe a two-stage computational protein design (CPD) methodology for the design of peptides binding to the FAT domain of the protein focal adhesion kinase. The first stage involves high-throughput CPD calculations with the Proteus software. The energies of the folded state are described by a physics-based energy function and of the unfolded peptides by a knowledge-based model that reproduces aminoacid compositions consistent with a helicity scale. The obtained sequences are filtered in terms of the affinity and the stability of the complex. In the second stage, design sequences are further evaluated by all-atom molecular dynamics simulations and binding free energy calculations with a molecular mechanics/implicit solvent free energy function.