New biochemical insight of conserved water molecules at catalytic and structural Zn2+ions in human matrix metalloproteinase-I: a study by MD-simulation.
Human matrix metalloproteinase (MMP)-1 or collagenase-1 plays a significant role in embryonic development, tissue remodeling, and is also involved in several diseases like arthritis, metastasis, etc. Molecular dynamics simulation studies on hMMP-1 X-ray structures (PDB Id. 1CGE, 1CGF, 1CGL, 1HFC, and 2TCL) suggest that the three conserved water molecules (WH/1, WI, WS) are coordinated with catalytic zinc (ZnC), and one water molecule (W) is associated at structural zinc ion (ZnS). Transition of the coordination geometry around ZnCfrom tetrahedral to octahedral and tetrahedral to trigonal bipyramidal at ZnSare also observed during the dynamics. Recognition of two zinc ions through water mediated bridges (ZnC- WH(W1)…W2….H183- ZnS) and stabilization of secondary coordination zone around the metal ions indicates the possibility of ZnC…ZnScoupled catalytic mechanism in hMMP-I. This study not only reveals a functionally important role of conserved water molecules in hMMP-I but also highlights the involvement of other non catalytic residues, such as S172 and D170 in the catalytic mechanism. The results obtained in this study could be relevant for importance of conserved water mediated recognition site of the sequence residue id. 202(RWTNNFREY)210, interaction of W(tryptophan)203 to zinc bound histidine, their influence on the water molecules that are involved in bridging between ZnCand ZnS, and structure-based design of specific hMMP inhibitors. Graphical abstract Water mediated recognition of structural and catalytic zinc ions of hMMP-1 structure (MD simulatated conformation).
Department of Chemistry, National Institute of Technology-Durgapur, Durgapur, 713209, India.
Bornali
B
Chakrabarti
Department of Chemistry, National Institute of Technology-Durgapur, Durgapur, 713209, India.|Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB21EW, UK.
Hridoy R
HR
Bairagya
Department of Chemistry, National Institute of Technology-Durgapur, Durgapur, 713209, India. bpmk2@yahoo.com.
Bishnu P
BP
Mukhopadhyay
Department of Computational and Data Sciences Indian Institute of Science, Laboratory for Structural Biology and Bio-computing, Bangalore, 560 012, India.
K
K
Sekar
D001665:Binding Sites / Q000502:physiology; D002412:Cations / Q000737:chemistry; D018360:Crystallography, X-Ray; D006639:Histidine / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry* / Q000648:ultrastructure; D056004:Molecular Dynamics Simulation; D014867:Water / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry*
D002412:Cations; D014867:Water; D006639:Histidine; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D015032:Zinc
Matrix metalloproteinase; Mechanism; Molecular dynamics; Zn ions