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Alternative interdomain configurations of the full-length MMP-2 enzyme explored by molecular dynamics simulations
1Departamento de Química Física y Analítica, Julián Clavería 8, Universidad de Oviedo, Oviedo (Asturias), 33006 Spain. diazfnatalia@uniovi.es
Abstract:
Conformational freedom between the different domains of the matrix metalloproteinase family of enzymes has been repeatedly invoked to explain the mechanism of hydrolysis of some of their most complex macromolecular substrates. This proposed interdomain motion has been experimentally confirmed to occur in solution for matrix metalloproteinases MMP-1, MMP-9, and MMP-12. In this work, we computationally assess the likely conformational freedom in aqueous solution of the full-length form of the MMP-2 enzyme in the absence of its pro-peptide domain. To this end, we perform molecular dynamics (MD) simulations and approximate free energy analyses in four different arrangements of the protein domains that correspond to (a) the compact conformation observed in the X-ray structure; (b) an initially elongated structure in which the hemopexin (HPX) domain is separated from the catalytic (CAT) and fibronectin domains; and (c-d) two alternative conformations suggested by protein-protein docking calculations. Overall, our results indicate that the interdomain flexibility is very likely a general property of the MMP-2 enzyme in solution.
Insights
Matrix metalloproteinase-2 (MMP-2) exhibits significant interdomain flexibility in solution. This conformational freedom is likely a general characteristic of MMP-2, impacting its function.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Biology
Background:
- Interdomain flexibility is crucial for matrix metalloproteinases (MMPs) to hydrolyze complex substrates.
- Experimental evidence confirms interdomain motion in MMP-1, MMP-9, and MMP-12.
Purpose of the Study:
- To computationally investigate the conformational freedom of full-length MMP-2 in aqueous solution.
- To assess interdomain flexibility in MMP-2, excluding the pro-peptide domain.
Main Methods:
- Molecular dynamics (MD) simulations were employed.
- Approximate free energy analyses were conducted.
- Simulations covered four distinct protein domain arrangements, including X-ray structure conformation, elongated states, and docking-derived conformations.
Main Results:
- Computational simulations suggest significant interdomain flexibility for MMP-2 in solution.
- The hemopexin (HPX) domain showed potential for separation from catalytic (CAT) and fibronectin domains.
- Flexibility appears to be a characteristic feature of MMP-2's behavior.
Conclusions:
- Interdomain flexibility is highly probable for MMP-2 in aqueous solution.
- This flexibility is likely a general property of the MMP-2 enzyme.
- Findings contribute to understanding MMP-2's mechanism of action and substrate interaction.
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