Long-Range Changes in Neurolysin Dynamics Upon Inhibitor Binding

Crystal structures of neurolysin, a zinc metallopeptidase, do not show a significant conformational change upon the binding of an allosteric inhibitor. Neurolysin has a deep channel where it hydrolyzes a short neuropeptide neurotensin to create inactive fragments and thus controls its level in the tissue. Neurolysin is of interest as a therapeutic target since changes in neurotensin level have been implicated in cardiovascular disorders, neurological disorders, and cancer, and inhibitors of neurolysin have been developed. An understanding of the dynamical and structural differences between apo and inhibitor-bound neurolysin will aid in further design of potent inhibitors and activators. For this purpose, we performed several molecular dynamics (MD) simulations for both apo and inhibitor-bound neurolysin. A machine learning method (Linear Discriminant Analysis) is applied to reveal differences between the apo and inhibitor-bound ensembles in an automated way, and large differences are observed on residues ...