Insight towards the conserved water mediated recognition of catalytic and structural Zn(+2) ions in human Matrix Metalloproteinase-8 enzyme: A study by MD-simulation methods
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Bornali Chakrabarti1, Hridoy R Bairagya, Deepak Kr Mishra
1Department of Chemistry, National Institute of Technology, Durgapur - 713 209, W.B. India.
Abstract:
Human matrix metalloproteinase-8 (hMMP-8) plays a important role in the progression of colorectal cancer, metastasis, multiple sclerosis and rheumetoid arthritis. Extensive MD-simulation of the PDB and solvated structures of hMMP-8 has revealed the presence of few conserved water molecules around the catalytic and structural zinc (ZnC and ZnS) ions. The coordination of two conserved water molecules (W and WS) to ZnS and the H-bonding interaction of WS to S151 have indicated the plausible involvement of that metal ion in the catalytic process. Beside this the coupling of ZnC and ZnS metal ions (ZnC - W(H) (W(1))…..W(2) ….H(162) - ZnS) through two conserved hydrophilic centers (occupied by water molecules) may also provide some rational on the recognition of two zinc ions which were separated by ~13 Å in their X-ray structures. This unique recognition of both the Zn(+2) ions in the enzyme through conserved water molecules may be implemented/ exploited for the design of antiproteolytic agent using water mimic drug design protocol.
Insights
Human matrix metalloproteinase-8 (hMMP-8) is crucial in diseases like cancer and arthritis. Conserved water molecules bridge zinc ions, suggesting a new strategy for designing antiproteolytic drugs.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Human matrix metalloproteinase-8 (hMMP-8) is implicated in colorectal cancer, metastasis, multiple sclerosis, and rheumatoid arthritis.
- Understanding the role of metal ions and their coordination environment is key to enzyme function and drug design.
Purpose of the Study:
- To investigate the role of conserved water molecules in the coordination and function of zinc ions in hMMP-8.
- To explore the potential of water molecules as mediators for drug design targeting hMMP-8.
Main Methods:
- Extensive molecular dynamics (MD) simulations of PDB and solvated hMMP-8 structures.
- Analysis of conserved water molecules around catalytic (ZnC) and structural (ZnS) zinc ions.
Main Results:
- Identified conserved water molecules coordinating to ZnS and interacting with S151, suggesting involvement in catalysis.
- Observed coupling of ZnC and ZnS ions via water molecules, explaining their separation in X-ray structures.
- Highlighted the role of water molecules in recognizing and bridging the two zinc ions.
Conclusions:
- Conserved water molecules play a critical role in the structural and functional aspects of hMMP-8.
- The water-mediated recognition of zinc ions offers a novel target for designing antiproteolytic agents.
- Water mimic drug design protocols can be exploited for developing new therapeutic strategies against hMMP-8 related diseases.
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