Molecular Dynamics Simulations of Matrix Metalloproteinase 13 and the Analysis of the Specificity Loop and the S1'-Site.

The specificity loop of Matrix Metalloproteinases (MMPs) is known to regulate recognition of their substrates, and the S1'-site surrounded by the loop is a unique place to address the selectivity of ligands toward each MMP. Molecular dynamics (MD) simulations of apo-MMP-13 and its complex forms with various ligands were conducted to identify the role of the specificity loop for the ligand binding to MMP-13. The MD simulations showed the dual role of T247 as a hydrogen bond donor to the ligand, as well as a contributor to the formation of the van der Waal surface area, with T245 and K249 on the S1'-site. The hydrophobic surface area mediated by T247 blocks the access of water molecules to the S1'-site of MMP-13 and stabilizes the ligand in the site. The F252 residue is flexible in order to search for the optimum location in the S1'-site of the apo-MMP-13, but once a ligand binds to the S1'-site, it can form offset π-π or edge-to-π stacking interactions with the ligand. Lastly, H222 and Y244 provide the offset π-π and π-CH(Cβ) interactions on each side of the phenyl ring of the ligand, and this sandwiched interaction could be critical for the ligand binding to MMP-13.