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

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.