Effects of the Nature of Metal Ion, Protein and Substrate on the Catalytic Center in Matrix Metalloproteinase‐1: Insights from Multilevel MD, QM/MM and QM Studies

Abstract

The front cover artwork is provided by Dr. Karabencheva‐Christova's group at Michigan Technological University. The image shows the multilevel molecular dynamics (MD), quantum mechanics/molecular mechanics (QM/MM) and quantum mechanics (QM) study on matrix metalloproteinase‐1 (MMP‐1). Read the full text of the Article at 10.1002/cphc.202100680.

Multiscale QM/MM modelling of catalytic systems with ChemShell

“…A combination of ChemShell QM/MM simulations and serial crystallography, which provides a ''movie'' of the reduction process in a protein crystal, yield complementary information on the system, resulting in a full description of the reaction mechanism. 107 The flexibility of QM/MM approaches to describe a wide range of metal cofactors is demonstrated by recent ChemShell applications on magnesium-dependent taxadiene synthase 108 and ala-glu-epimerase, 109 xyloside a-1,3-xylosyltransferase (where magnesium was modelled in place of manganese), 110 nickel-containing quercetinases, 111,112 tungsten-dependent benzoyl-coenzyme A reductase 113 and zinc-dependent leukotriene A 4 hydrolase, 114 matrix metalloproteinase-1 115 and matrix metalloproteinase-9. 116 Zhao et al used ChemShell to find the most favourable pathway for catalysis of N-N bond formation by a family of zinc-binding cupin proteins.…”

Mechanism of the Early Catalytic Events in the Collagenolysis by Matrix Metalloproteinase‐1

“…In addition to the experimental studies, some aspects of the structure-function relationships and catalysis in MMPs have been studied computationally. [16,17,[30][31][32][33] Such studies have been performed often with small substrate models, which certainly provided valuable mechanistic insights; however, they ignored the effects of the flexibility of the large THP substrate and its interactions with the MMP-1 enzyme. Nevertheless, the atomistic nature of the conformational transitions, their free energy cost, and the associated changes in the coordination state of the catalytic zinc(II) that lead to formation of the catalytically productive MMP-1 ES complex remain unknown.…”

“…Although the coordination state of the catalytic zinc(II) in MMPs and in particular in MMP‐1 has been intensively studied, there is still lack of information as to how the coordination state is influenced by the complex conformational changes involved in the THP binding and the formation of the catalytically productive MMP‐1•THP. In addition to the experimental studies, some aspects of the structure‐function relationships and catalysis in MMPs have been studied computationally [16,17,30–33] . Such studies have been performed often with small substrate models, which certainly provided valuable mechanistic insights; however, they ignored the effects of the flexibility of the large THP substrate and its interactions with the MMP‐1 enzyme.…”