Long-Range Conformational Response of a PDZ Domain to Ligand Binding and Release: A Molecular Dynamics Study

The binding of a ligand to a protein may induce long-range structural or dynamical changes in the biomacromolecule even at sites physically well separated from the binding pocket. A system for which such behavior has been widely discussed is the PDZ2 domain of human tyrosine phosphatase 1E. Here, we present results from equilibrium trajectories of the PDZ2 domain in the free and ligand-bound state, as well as nonequilibrium simulations of the relaxation of PDZ2 after removal of its peptide ligand. The study reveals changes in inter-residue contacts, backbone dihedral angles, and C-alpha positions upon ligand release. Our findings show a long-range conformational response of the PDZ2 domain to ligand release in the form of a collective shift of the secondary structure elements alpha(2), beta(2), beta(3), alpha(1)-beta(4), and the C terminal loop relative to the rest of the protein away from the N-terminus, and a shift of the loops beta(2)-beta(3) and beta(1)-beta(2) in the opposite direction. The shifts lead to conformational changes in the backbone, especially in the beta(2)-beta(3) loop but also in the beta(5)-alpha(2) and the alpha(2)-beta(6) loop, and are accompanied by changes of inter-residue contacts mainly within the beta(2)-beta(3) loop as well as between the alpha(2) helix and other segments. The residues showing substantial changes of inter-residue contacts, backbone conformations, or C-alpha positions are considered key residues for the long-range conformational response of PDZ2. By comparing these residues with various sets of residues highlighted by previous studies of PDZ2, we investigate the statistical correlation of the various approaches. Interestingly, we find a considerable correlation of our findings with several works considering structural changes but no significant correlations with approaches considering energy flow or networks based on inter-residue energies.