Effect of ligand binding on the dynamics of trypsin. Comparison of different approaches

• Effect of ligand binding on dynamics of trypsin was studied using MD simulation.
• Ligands increase the correlation the active center residues and the substrate-binding site.
• S1 pocket residues participate in signal transduction from the substrate-binding site to the active center.
• The active center residues have the zero amplitude in the slowest fluctuations acting as hinges or anchors.

The intramolecular signal transduction induced by the binding of ligands to trypsin was investigated by molecular dynamics simulations. Ligand binding changes the residue-residue interaction energies and suppresses the mobility of loops that are in direct contact with the ligand. The reduced mobility of these loops results in the altered flexibility of the nearby loops and thereby transmits the information from ligand binding site to the remote sites. The analysis of the flexibility of all residues confirmed the coupling between loops L1 (185–188) and L2 (221–224) and the residues in the active center. The significance of S1 pocket residues for the signal transduction from the active center to the substrate-binding site was confirmed by the dynamical network and covariance matrix analyses. Gaussian network model and principal component analysis demonstrated that the active center residues had zero amplitude in the slowest fluctuations acting as hinges or anchors. Overall, our results provide a new insight into protein–ligand interactions and show how the allosteric signaling may occur.

Ligand binding induces the change of the residue-residue interaction energy and suppresses the mobility of loops that produces the wave of perturbations spreading along the protein.Figure optionsDownload high-quality image (100 K)Download as PowerPoint slide