title: Unraveling the molecular structure of the catalytic domain of matrix metalloproteinase-2 in complex with a triple-helical peptide by means of molecular dynamics simulations.
abstract: Herein, we present the results of a computational study that employed various simulation methodologies to build and validate a series of molecular models of a synthetic triple-helical peptide (fTHP-5) both in its native state and in a prereactive complex with the catalytic domain of the MMP-2 enzyme. First, the structure and dynamical properties of the fTHP-5 substrate are investigated by means of molecular dynamics (MD) simulations. Then, the propensity of each of the three peptide chains in fTHP-5 to be distorted around the scissile peptide bond is assessed by carrying out potential of mean force calculations. Subsequently, the distorted geometries of fTHP-5 are docked within the MMP-2 active site following a semirigid protocol, and the most stable docked structures are fully relaxed and characterized by extensive MD simulations in explicit solvent. Following a similar approach, we also investigate a hypothetical ternary complex formed between two MMP-2 catalytic units and a single fTHP-5 molecule. Overall, our models for the MMP-2/fTHP-5 complexes unveil the extent to which the triple helix is distorted to allow the accommodation of an individual peptide chain within the MMP active site.
authors.affiliation: Departamento de Química Física y Analítica, Universidad de Oviedo , Julián Clavería 8, Oviedo (Asturias) 33006, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Díaz
authors.forename: Dimas
authors.initials: D
authors.lastname: Suárez
authors.forename: Haydeé
authors.initials: H
authors.lastname: Valdés
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D024043:Collagen Type II / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
chemical_list: C499177:COL2A1 protein, human; D024043:Collagen Type II; D010446:Peptide Fragments; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2