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

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.