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<sub>α</sub> 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 α<sub>2</sub>, β<sub>2</sub>, β<sub>3</sub>, α<sub>1</sub>-β<sub>4</sub>, and
the C terminal loop relative to the rest of the protein away from
the N-terminus, and a shift of the loops β<sub>2</sub>-β<sub>3</sub> and β<sub>1</sub>-β<sub>2</sub> in the opposite
direction. The shifts lead to conformational changes in the backbone,
especially in the β<sub>2</sub>-β<sub>3</sub> loop but
also in the β<sub>5</sub>-α<sub>2</sub> and the α<sub>2</sub>-β<sub>6</sub> loop, and are accompanied by changes
of inter-residue contacts mainly within the β<sub>2</sub>-β<sub>3</sub> loop as well as between the α<sub>2</sub> helix and
other segments. The residues showing substantial changes of inter-residue
contacts, backbone conformations, or C<sub>α</sub> 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
