Matrix metalloproteinase 1 (MMP-1) is a conformationally flexible and structurally complex multidomain metalloproteinase comprised of a catalytic domain (CAT), a hemopexin-like (HPX) domain, and a linker region. It catalyzes collagen hydrolysis, a critical process in normal tissue functioning, maintenance, and repair; however, abnormal collagenolysis results in numerous pathological conditions, including cancer, tumor growth and metastasis, and fibrosis. The availability of experimentally determined structures- an X-ray crystallographic one and an NMR spectroscopic one in solution provide important structural information about MMP-1. This information, however, is far from being completely informative for the enzyme-substrate (ES) complex of MMP-1. Moreover, the crystallographic structure captured the enzyme in a “closed” conformational state, with the substrate bound in a non-productive orientation for hydrolysis, and the NMR structure lacks the coordinates of the substrate. Notably, the experimentally derived structures are averaged ones, missing the contribution of the conformational dynamics, a fundamental property of proteins relating their structure to function. To define major conformational changes that occur in the MMP-1 ES complex at the atomic scale of detail, we performed well-tempered (WT) metadynamics simulations combined with quantum mechanics/molecular mechanics (QM/MM) metadynamics to reveal the transition of the “open” conformation of the MMP-1●THP complex to the catalytically competent “closed” conformation. Understanding the process of formation of a catalytically competent enzyme-substrate complex in MMP-1 is vital for understanding the molecular pathology of MMP-1 related diseases and providing new horizons for the design of specific and effective MMP-1 inhibitors.

Large scale conformational dynamics of Matrix metalloproteinase-1●triple-helical peptide complex

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