Abstract
The human ceruloplasmin (hCP) is the copper containing ferroxidase enzyme with multifunctional activities (NO-oxidase, NO2-synthase,oxidation of neurotransmitters including antioxidants). Therefore, it is of interest to probe the multi-domain hCP using moleculardynamics simulation. Results explain the role played by several conserved water centers in the intra and inter-domain recognition throughH-bond interaction with the interacting residues. We observed seventeen conserved water centers in the inter-domain recognition. Weshow that five invariant water centers W13, W14, W18, W23 and W26 connect the Domain 5 to Domain 4 (D5…W…W4). We also show thatfive other water centers W19, W20, W27, W30 and W31 connects the Domain 5 to Domain 6 (D5…W…W6) that is unique in the simulatedform. The W7 and W32 water centers are involved in the D1…W…W6 recognition. This is important for the water-mediated interaction ofGlu1032 to the trinuclear copper cluster present at the interface between these domains. The involvement of W10 water center in theD3…W10…D4 recognition through Gln552…W10…His667 H-bond interaction is critical in the complexation of CP with myeloperoxidase(Mpo). These observations provide insights to the molecular recognition of hCP with other biomolecules in the system.
Highlights
Ceruloplasmin is a copper containing ferroxidase enzyme
The coupling between acidic and basic residues through conserved water molecules is thought to be an important aspect for intra/inter-domain stabilization, in few cases those water centers may participate in the redox coupling or proton exchange reaction.MDsimulation studies have provided the key insights into the importance of conserved water molecules in the intra/inter-domain recognition and their influence to the stability of CP structure
The structure of ceruloplasmin is mainly buildup with the six domains (D1-D6) having sequences: 1-192 (D1), 193-340 (D2), 347553(D3), 554-703 (D4), 704-884(D5) and 891-1040 (D6) [24]
Summary
Ceruloplasmin (hCP) is a copper containing ferroxidase enzyme. Beside the antioxidant properties of enzyme it shows different activities e.g., oxidation of biogenic monoamines, NO-oxidase, NO2-synthase [1], glutathione-linked peroxidase [2] and able to prevent oxidative damage to protein, DNA and lipids [3] etc, in most of the cases the reaction mechanisms are still unknown [4]. The X-ray structures have shown the presence of a trinuclear copper cluster and three mononuclear copper centers within the 3D-arrangement of six domains in the enzyme. Further MD-simulation studies have indicated the role of conserved water molecules in the interaction with trinuclear and mononuclear. The structural and functional role of conserved water molecules and their endowment towards the intra and inter-domain recognition of proteins or metalloenzymes are well known [7,8]. Due to complexity in the structure of CP, the role of conserved water molecules in inter-domain recognition, their influence to the stability of overall structure or function is still not clear due to the limitations of resolution in the available crystal structures. Investigation of conserved water mediated recognition between Glu552 to His667, alongwith the conformational dynamics of His667 and Trp669 have been made because of their importance in the complexation of ceruloplasmin with macromolecule myeloperoxidase (Mpo)
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