D. Li, S-W Chang
National Taiwan University,
Keywords: aggrecan, catalytic mechanism, binding affinity, bottom-up computational mechanics approach
Summary:Cartilage is an important smart material which provides crucial mechanical properties for our body. Many diseases are associated with abnormal aggrecan degradation in articular cartilage. Aggrecan degradations are mainly controlled by matrix metalloproteinase-8 (MMP8). MMP8 cleaves at the catalytic cleavage site of Glu373-374Ala in the aggrecan core protein, with another potential cleavage site at Glu419-420Ala, however, left uncut. The catalytic mechanism of how the MMP8 recognizes the catalytic cleavage site has not yet been revealed. Understanding how nature design materials to be degraded at only specific regions can enable the design of new synthetic smart materials for many engineering applications. To investigate this, we use a bottom-up computational mechanics approach to explore this conundrum. We found that the two key residues in the vicinity of the catalytic site, arginine in P2’ and glycine in P3’ play an important role in forming a stable binding pose of MMP8-Actual_peptide complex. For the potential cleavage site, the arginine is replaced with Threonine and the glycine is replaced with arginine, resulting in the unstable binding pose of MMP8-Potential_peptide complex. Our results suggest that MMP8 is able to recognize the molecular structure of the catalytic cleavage site and only cleave Glu373-374Ala in the aggrecan core protein. By calculating the binding affinity between MMP8 and aggrecan core protein, we find that the binding energy of MMP8-Actual_peptide complex is higher than the binding energy of MMP8-Potential_peptide complex. We hypothesize that the stable binding structure of the catalytic cleavage site of aggrecan core protein makes MMP8 stay in an “active” state, and then hydrolyze the scissile bond of aggrecan core protein. On the contrary, unstably binding between the potential cleavage site of aggrecan core protein and MMP8 makes MMP8 stay in an “inactive” state. Our results provide fundamental insights into the catalytic mechanism of biomaterials in cartilage at the molecular and nanoscale level.