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 S10-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 pi-pi or edge-to-pi stacking interactions with the ligand. Lastly, H222 and Y244 provide the offset pi-pi and pi-CH(C beta) 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.

Automated summary

The specificity loop of MMPs, particularly the S10-site, plays a crucial role in ligand binding and substrate recognition. MD simulations of apo-MMP-13 and its complexes with ligands revealed the involvement of specific residues, such as T247, in hydrogen bonding and van der Waals interactions with ligands. T247 also contributes to the formation of a hydrophobic surface that stabilizes ligands in the S1'-site of MMP-13. F252 residue exhibits flexibility to optimize ligand positioning in the S1'-site, but can form offset pi-pi or edge-to-pi stacking interactions upon ligand binding. H222 and Y244 facilitate offset pi-pi and pi-CH(C beta) interactions on either side of the ligand's phenyl ring, which is crucial for ligand binding to MMP-13.