Conformation and Domain Movement Analysis of Human Matrix Metalloproteinase-2: Role of Associated Zn2+ and Ca2+ Ions.

Leah Voit-Ostricki,Charles R Watts,Sándor Lovas

doi:10.3390/ijms20174194

Abstract

Matrix metaloproteinase-2 (MMP-2) is an extracellular Zn2+ protease specific to type I and IV collagens. Its expression is associated with several inflammatory, degenerative, and malignant diseases. Conformational properties, domain movements, and interactions between MMP-2 and its associated metal ions were characterized using a 1.0 µs molecular dynamics simulation. Dihedral principle component analysis revealed ten families of conformations with the greatest degree of variability occurring in the link region connecting the catalytic and hemopexin domains. Dynamic cross-correlation analysis indicated domain movements corresponding to the opening and closing of the hemopexin domain in relation to the fibronectin and catalytic domains facilitated by the link region. Interaction energies were calculated using the molecular mechanics Poisson Boltzman surface area-interaction entropy (MMPBSA-IE) analysis method and revealed strong binding energies for the catalytic Zn2+ ion 1, Ca2+ ion 1, and Ca2+ ion 3 with significant conformational stability at the binding sites of Zn2+ ion 1 and Ca2+ ion 1. Ca2+ ion 2 diffuses freely away from its crystallographically defined binding site. Zn2+ ion 2 plays a minor role in conformational stability of the catalytic domain while Ca2+ ion 3 is strongly attracted to the highly electronegative sidechains of the Asp residues around the central β-sheet core of the hemopexin domain; however, the interacting residue sidechain carboxyl groups are outside of Ca2+ ion 3′s coordination sphere.

Highlights

Matrix metaloproteinase-2 (MMP-2) is a 550 amino acid residue extracellular Zn2+ protease that degrades type I and IV collagens [1,2]
The goal of the current study is to evaluate the dynamic stability of the divalent metal ions (2 Zn2+ and 3 Ca2+) reported in the X-ray crystal structure protein databank (PDB) ID: 1CK7 and examine the domain movements within MMP-2 using 1.0 μs NPT molecular dynamics (MD) simulations at physiological temperature (310 K)
The radius of gyration (Rg) and center-of mass (COM) distance data are consistent with inter-domain motions between Cat/Fib and Hpx and the presence of inter-domain motions and the sampling of more extended conformations of MMP-2 in solution compared to the more compact X-ray crystal structure (PDB ID: 1CK7) which has Rg: 2.77 nm, Cat-Hpx COM distance: 3.81 nm, and Fib-Hpx COM distance: 2.00 nm [13]

Summary

Introduction

Matrix metaloproteinase-2 (MMP-2) is a 550 amino acid residue extracellular Zn2+ protease that degrades type I and IV collagens [1,2]. As shown in Figure 1; MMP-2 has three domains, catalytic (Cat), fibronectin (Fib), and hemopexin (Hpx) and five crystallographically assigned divalent cations (two Zn2+ and three Ca2+) [13]. The Fib domain (Glu217 through Gln393) is inserted within the catalytic domain between the β5-sheet and α2-helix and contains three type II fibronectin fingers consisting of two antiparallel β-sheets connected by a short α-helix forming a three prong treble hook-like arrangement. This domain and its arrangement may play a crucial role in substrate binding and presentation to the catalytic site.

Objectives

Methods

Results

Conclusion