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Structural Insight into the Prolyl Hydroxylase PHD2: A Molecular Dynamics and DFT Study
Author(s) -
Wick Christian R.,
Lanig Harald,
Jäger Christof M.,
Burzlaff Nicolai,
Clark Timothy
Publication year - 2012
Publication title -
european journal of inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 136
eISSN - 1099-0682
pISSN - 1434-1948
DOI - 10.1002/ejic.201200391
Subject(s) - chemistry , molecular dynamics , molecular mechanics , carboxylate , computational chemistry , triad (sociology) , stereochemistry , crystallography , psychology , psychoanalysis
We describe computational studies of the mode of action of the prolyl hydroxylase domain containing protein (PHD2). Long‐term molecular dynamics (MD) simulations were performed to investigate the rigidity of the crystallographically observed conformations of PHD2 in solution. We also describe the influence of the C‐terminal oxygen‐dependent degradation domain (CODD) of hypoxia inducible factor 1α (HIF‐1α) on the overall behaviour of the protein, including the effect of the natural ligand 2‐oxoglutarate (2OG) and an isoquinoline inhibitor. To study the geometry of the 2‐His‐1‐carboxylate facial triad and its dependency on the protein environment, we performed DFT calculations on model systems and compared them with quantum mechanics/molecular mechanics (QM/MM) gas‐phase energy minimisations, which allowed us to treat the whole protein. The combination of these methods provides insight into the behaviour of the 2‐His‐1‐carboxylate facial triad with 2OG and an inhibitor of PHD2 on the atomistic scale.