title: Mapping intermolecular interactions and active site conformations: from human MMP-1 crystal structure to molecular dynamics free energy calculations.
abstract: The zinc-dependent Matrix Metalloproteinases (MMPs) found within the extracellular matrix (ECM) of vertebrates are linked to pathological processes such as arthritis, skin ulceration and cancer. Although a general backbone proteolytic mechanism is understood, crystallographic data continue to suggest an active site that is too narrow to encompass the respective substrate. We present a fully parameterised Molecular Dynamics (MD) study of the structural properties of an MMP-1-collagen crystallographic structure (Protein Data Bank - 4AUO), followed by an exploration of the free energy surface of a collagen polypeptide chain entering the active site, using a combined meta-dynamics and umbrella sampling (MDUS) approach. We conclude that the interactions between MMP-1 and the collagen substrate are in good agreement with a number of experimental studies. As such, our unrestrained MD simulations and our MDUS results, which indicate an energetic barrier for a local uncoiling and insertion event, can inform future investigations of the collagen-peptide non-bonded association steps with the active site prior to proteolytic mechanisms. The elucidation of such free energy barriers provides a better understanding of the role of the enzyme in the ECM and is important in the design of future MMP inhibitors.
authors.affiliation: a Department of Chemistry , University College London , London , UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Nash
authors.affiliation: b Institute of Orthopaedics & Musculoskeletal Science , University College London , London , UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Birch
authors.affiliation: a Department of Chemistry , University College London , London , UK.|c School of Chemistry , Cardiff University , Cardiff , UK.
authors.forename: Nora H
authors.initials: NH
authors.lastname: de Leeuw
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D012997:Solvents
chemical_list: D008024:Ligands; D012997:Solvents; D020781:Matrix Metalloproteinase 1
keywords: collagenase; free energy; matrix-metalloproteinase; metzincin; proteinase; zinc