Computational Design of PDZ-Peptide Binding

This chapter describes two computational methods for PDZ–peptide binding: high-throughput computational protein design (CPD) and a medium-throughput approach combining molecular dynamics for conformational sampling with a Poisson–Boltzmann (PB) Linear Interaction Energy for scoring. A new CPD method is outlined, which uses adaptive Monte Carlo simulations to efficiently sample peptide variants that tightly bind a PDZ domain, and provides at the same time precise estimates of their relative binding free energies. A detailed protocol is described based on the Proteus CPD software. The medium-throughput approach can be performed with standard MD and PB software, such as NAMD and Charmm. For 40 complexes between Tiam1 and peptide ligands, it gave high a2ccuracy, with mean errors of around 0.5 kcal/mol for relative binding free energies and no large errors. It requires a moderate amount of parameter fitting before it can be applied, and its transferability to other protein families is still untested.