Mapping intermolecular interactions and active site conformations: from human MMP-1 crystal structure to molecular dynamics free energy calculations

J Biomol Struct Dyn. 2017 Feb;35(3):564-573. doi: 10.1080/07391102.2016.1153521. Epub 2016 Apr 25.

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.

Keywords: collagenase; free energy; matrix-metalloproteinase; metzincin; proteinase; zinc.

MeSH terms

  • Binding Sites*
  • Catalytic Domain*
  • Humans
  • Hydrogen Bonding
  • Ligands
  • Matrix Metalloproteinase 1 / chemistry*
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Conformation*
  • Protein Interaction Domains and Motifs*
  • Solvents

Substances

  • Ligands
  • Solvents
  • Matrix Metalloproteinase 1