title: Molecular dynamics simulations of the active matrix metalloproteinase-2: positioning of the N-terminal fragment and binding of a small peptide substrate.
abstract: Herein we use different computational methods to study the structure and energetic stability of the catalytic domain of the active MMP-2 enzyme considering two different orientations of its N-terminal coil. The first orientation is largely solvent accessible and corresponds to that observed in the 1CK7 crystal structure of the proenzyme. In the second orientation, the N-terminal coil is packed against the Omega-loop and the alpha3-helix of the MMP-2 enzyme likewise in the so-called "superactivated" form of other MMPs. Binding to the MMP-2 catalytic domain of a short peptide substrate, which mimics the sequence of the alpha1 chain of collagen type I, is also examined considering again the two configurations of the N-terminal coil. All these MMP-2 models are subject to 20 ns molecular dynamics (MD) simulations followed by MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) calculations. The positioning of the N-terminal coil in the "superactivated" form is found to be energetically favored for the MMP-2 enzyme. Moreover, this configuration of the N-terminal moiety can facilitate the binding of peptide substrates. Globally, the results obtained in this study could be relevant for the structural-based design of specific MMP inhibitors.
authors.affiliation: Departamento de Química Física y Analítica, Universidad de Oviedo, Oviedo (Asturias), Spain. diazfnatalia@uniovi.es
authors.forename: Natalia
authors.initials: N
authors.lastname: Díaz
authors.forename: Dimas
authors.initials: D
authors.lastname: Suárez
mesh_terms: D000595:Amino Acid Sequence; D002384:Catalysis; D020134:Catalytic Domain; D003198:Computer Simulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors; D057927:Hydrophobic and Hydrophilic Interactions; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry* / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D017433:Protein Structure, Secondary; D012997:Solvents; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D012997:Solvents; D020778:Matrix Metalloproteinase 2