Mechanism of the Early Catalytic Events in the Collagenolysis by Matrix Metalloproteinase-1

Abstract

The front cover artwork is provided by Dr. Karabencheva-Christova's group at Michigan Technological University. The images show the initially formed and the catalytically productive conformations of MMP-1 complex with the Triple Helical Peptide (THP), the free energy profile connecting them as well as the coordination geometry of the catalytic zinc (II). The background shows the collagen macromolecule. Read the full text of the Research Article at 10.1002/cphc.202200649.

Figure 1.

NMR-derived MMP-1●THP structure. Pictured are the CAT domain (in red), HPX domain (in blue), linker region (in green), and THP substrate (in yellow). The catalytic Zn(II) site with coordinating histidine residues is shown in the zoomed-in view in the inset.

Figure 2.

MMP-1 structure showing (a) the different structural elements of the CAT and HPX domains, (b, left) the catalytic Zn(II) site of open-4C, and (b, right) the catalytic Zn(II) site of open-5C.

Figure 3.

(a) Hydrogen bonding interactions of catalytic Zn(II)-coordinated His228 with Ser227 and Gln774. (b) Stacking interactions between catalytic Zn(II)-coordinated His218 and Tyr240 in open-4C (in red) and open-5C (in yellow). (c) Hydrophobic interactions between catalytic Zn(II) coordinated His228 and Pro238 in open-4C (in red) and open-5C (in yellow). (d) Hydrophobic interactions between catalytic Zn(II) coordinated His228 and Ile776 in open-4C (in red) and open-5C (in yellow). The interactions in panels b-d were evaluated considering the distances between the center of masses of the side chains atoms of the involved residues. The graphics of the respective distances as a function of time are presented in Figures S8-S10 of the SI.

Figure 4.

Correlated and anti-correlated motions of key structural elements of the open forms of MMP-1●THP complex. Panel (a) represents a correlated motion between S-loop and blade IV of HPX; a correlated motion between blade I of the HPX and residues from α-helix hA and β1-β2; a correlated motion between the linker residues and the residues that constitute α-helix hA and β1-β2. Panel (b) shows an anti-correlated motion between V-B loop residues and blade II of HPX; and an anti-correlated motion between blade IV of the HPX and residues from α-helix hA and β1-β3. The DCCA graphs are presented in Figure S12 of the SI.

Figure 5.

(a) Distance between catalytic Zn(II) and carbonyl oxygen of scissile bond Gly (CV1). (b) FES as a function of CV1 for transition from open-4C (O4C) to closed-4C (C4C) form of MMP-1●THP ES complex. (c) FES as a function of CV1 for open-5C (O5C) transition.

Figure 6.

(a) Superposition of the averaged open-4C MMP-1●THP (green) from the standard MD and the averaged closed-4C structure (blue) from MetD simulations. (b) Superposition of the averaged closed-4C form the standard MD (red) and averaged closed-4C form (blue) from MetD.

Figure 7.

QM/MM MetD of the water dissociation from the catalytic Zn(II). (a) Dependence of the CV (distance between catalytic Zn(II) and the oxygen atom of the Zn(II) coordinating water molecule) as a function of time. (b) FES of the water dissociation as a function of the CV. (c) Geometries of RC1, TS1, and PC1.

Figure 8.

(a) Free energy profile for the coordination of scissile bond Gly carbonyl oxygen to the catalytic Zn(II). (b) The collective variable (CV) as a function of time. (c) Geometries of the RC2, TS2, and the PC2 for the formation of the catalytically competent five-coordinated closed form of MMP-1●THP complex.

Scheme 1.

Evolution of the Early Catalytic Events in the MMP-1●THP Complex.