Human neutrophil collagenase (HNC, MMP8) is one of the target enzymes for drug treatment of pathologic extracellular matrix degradation. Peptidomimetic inhibitors bind in the S-side of the enzyme active site occupying the S1 primary specificity pocket by their large hydrophobic side-chains. The crystal structure of the complex between the catalytic domain of MMP-8 and Pro-Leu-L-TrpP(OH)₂(PLTP) showed that this phosphonate inhibitor binds in the S side of the active site.

Figure 1: Crystal structure of the Human neutrophil collagenase (PDB code: 1I73).

This finding was unexpected since it represents the first example of accommodation of the bulky Trp indolyl chain in the S1 rather than in the S’1 sub-site. We have therefore studied the dynamical and structural factors favoring this uncommon mode of binding [1]. MD simulations performed on the uncomplexed enzyme show that its structure in aqueous solution is only slightly different from the crystal structure found in the complex with PLTP. The results from the MD simulations, performed on PLTP alternatively interacting with the S- or S’-side of the active site, have shown that the enzyme fluctuation increases in both cases. The main contribution to the overall enzyme fluctuation is given by the loop 164-173. The fluctuation of this loop is spread over more degrees of freedom when PLTP interacts with the S-side. This dynamical factor can enhance the preference of PLTP for the S subsites of MMP-8. MD simulations have shown that ligation of PLTP in the S subsites is further favored by better zinc chelation, a cation-p interaction at the S₃ subsite and unstrained binding conformations.

REFERENCE

1. M. Aschi, D. Roccatano, A. Di Nola, C. Gallina, E. Gavuzzo, G. Pochetti, M. Pieper, H. Tschesche, F. Mazza. Computational study of the catalytic domain of human neutrofil collagenase. Specific role of the S and S’ subsites in the interaction with a phophonate inhibitor. J. Comp. Aided Mol. Des., 16, 213-225 (2002).