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Use of Umbrella Sampling to Calculate the Entrance/Exit Pathway for Z-Pro-Prolinal Inhibitor in Prolyl Oligopeptidase

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Département de Physique and Regroupement Québécois sur les Matériaux de Pointe, Université de Montréal, C.P. 6128, succursale centre-ville, Montréal (Québec), Canada H3C 3J7
Department of Applied Mathematics, The University of Western Ontario, 1151 Richmond Street North, London (Ontario), Canada N6A 5B7
§ Department of Physics, Tampere University of Technology, P.O. Box 692, FI-33101 Tampere, Finland
Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FI-00014, University of Helsinki, Finland
Department of Chemistry, Aalto University, PO Box 6100, FI-02015, Aalto, Finland
Cite this: J. Chem. Theory Comput. 2011, 7, 6, 1583–1594
Publication Date (Web):April 29, 2011
Copyright © 2011 American Chemical Society

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    Prolyl oligopeptidase (POP), a member of the prolyl endopeptidase family, is known to play a role in several neurological disorders. Its primary function is to cleave a wide range of small oligopeptides, including neuroactive peptides. We have used force biased molecular dynamics simulation to study the binding mechanism of POP. We examined three possible binding pathways using Steered Molecular Dynamics (SMD) and Umbrella Sampling (US) on a crystal structure of porcine POP with bound Z-pro-prolinal (ZPP). Using SMD, an exit pathway between the first and seventh blade of the β-propeller domain of POP was found to be a nonviable route. US on binding pathways through the β-propeller tunnel and the TYR190-GLN208 flexible loop at the interface between both POP domains allowed us to isolate the flexible loop pathway as the most probable. Further analysis of that pathway suggests a long-range covariation of the interdomain H-bond network, which indicates the possibility of large-scale domain reorientation observed in bacterial homologues and hypothesized to also occur in human POP.

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