Recognition dynamics of trinuclear copper cluster and associated histidine residues through conserved or semi-conserved water molecules in human Ceruloplasmin: The involvement of aspartic and glutamic acid gates

2017-11-17T11:16:35Z (GMT) by Bishnu Prasad Mukhopadhyay
<p>Human Ceruloplasmin belongs to the family of multi-copper oxidases and it is involved in different physiological processes, copper ion transport, iron metabolism, iron homeostasis, and biogenic amine metabolism. MD-simulation studies have indicated the higher hydrophilic susceptibility of the trinuclear copper cluster in native CP compared to its oxygen bound form. The copper (T2/T3) atom Cu3047 of the cluster, which is close to T1 copper center Cu3052 (~13 Å) has a higher affinity for water molecules compared to other copper centers. The water molecules of W3, W4, W5, W9, and W12 conserved water sites are coordinated to Cu3047, where W3, W9, and W12 centers are found to play some crucial role in the stabilization of native trinuclear copper cluster. The hydrogen bonding interaction of Asp169, Glu112, Asp995, and Glu1032 residues with the copper-bound conserved water molecules (W3, W4, W5, W10, and W11) in native CP is observed to be unique. The conformational flexibility of Asp169 and Glu112 and their association with the copper-bound water molecules, but the absence of such interaction in O<sub>2</sub>-bound simulated structure of the enzyme is indicating some plausible rational on the role of these acidic residues in the gating of O<sub>2</sub> molecule in the native trinuclear Cu cluster of CP. The simulation results may shade some new light on the biochemistry/chemistry of CP, specially on the hydration dynamics of the trinuclear copper cluster.</p>