A minimalist chemical model of matrix metalloproteinases — Can small peptides mimic the more rigid metal binding sites of proteins?

•We studied a peptide corresponding to the catalytic zinc(II) binding site of MMP-13.•This peptide is able to mimic several basic features of the MMP active sites.•The peptide provides {3Nim} coordination environment for zinc(II).•The deprotonation of the zinc-bound water takes place near to the physiological pH.•The mixed-hydroxo complexes possess notable hydrolytic activity.

In order to mimic the active center of matrix metalloproteinases (MMPs), we synthesized a pentadecapeptide (Ac-KAHEFGHSLGLDHSK-NH2) corresponding to the catalytic zinc(II) binding site of human MMP-13. The multi-domain structural organization of MMPs fundamentally determines their metal binding affinity, catalytic activity and selectivity. Our potentiometric, UV-visible, CD, EPR, NMR, mass spectrometric and kinetic studies are aimed to explore the usefulness of such flexible peptides to mimic the more rigid metal binding sites of proteins, to examine the intrinsic metal binding properties of this naked sequence, as well as to contribute to the development of a minimalist, peptide-based chemical model of MMPs, including the catalytic properties. Since the multiimidazole environment is also characteristic for copper(II), and recently copper(II) containing variants of MMPs have been identified, we also studied the copper(II) complexes of the above peptide. Around pH 6–7 the peptide, similarly to MMPs, offers a {3Nim} coordination binding site for both zinc(II) and copper(II). In the case of copper(II), the formation of amide coordinated species at higher pH abolished the analogy with the copper(II) containing MMP variant. On the other hand, the zinc(II)-peptide system mimics some basic features of the MMP active sites: the main species around pH 7 (ZnH2L) possesses a {3Nim,H2O} coordination environment, the deprotonation of the zinc-bound water takes place near the physiological pH, it forms relatively stable ternary complexes with hydroxamic acids, and the species ZnH2L(OH) and ZnH2L(OH)2 have notable hydrolytic activity between pH 7 and 9.

Graphical abstractDespite the modest zinc binding affinity, the studied small, flexible peptide is able to mimic several basic features of the matrix metalloproteinase active sites: provides {3Nim} coordination environment, stable ternary complexes are formed with hydroxamic acids, the deprotonation of the zinc-bound water takes place around pH 7, and the mixed-hydroxo complexes possess notable hydrolytic activity.Figure optionsDownload full-size imageDownload as PowerPoint slide