Mapping intermolecular interactions and active site conformations: from human MMP-1 crystal structure to molecular dynamics free energy calculations

Nash, Anthony, Birch, Helen L. and de Leeuw, Nora ORCID: https://orcid.org/0000-0002-8271-0545 2017. Mapping intermolecular interactions and active site conformations: from human MMP-1 crystal structure to molecular dynamics free energy calculations. Journal of Biomolecular Structure and Dynamics 35 (3) , pp. 564-573. 10.1080/07391102.2016.1153521

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Abstract

The zinc-dependent Matrix Metalloproteinases (MMPs) found within the extracellular matrix (ECM) of vertebrates are linked to pathological processes such as arthritis, skin ulceration and cancer. Although a general backbone proteolytic mechanism is understood, crystallographic data continue to suggest an active site that is too narrow to encompass the respective substrate. We present a fully parameterised Molecular Dynamics (MD) study of the structural properties of an MMP-1-collagen crystallographic structure (Protein Data Bank – 4AUO), followed by an exploration of the free energy surface of a collagen polypeptide chain entering the active site, using a combined meta-dynamics and umbrella sampling (MDUS) approach. We conclude that the interactions between MMP-1 and the collagen substrate are in good agreement with a number of experimental studies. As such, our unrestrained MD simulations and our MDUS results, which indicate an energetic barrier for a local uncoiling and insertion event, can inform future investigations of the collagen-peptide non-bonded association steps with the active site prior to proteolytic mechanisms. The elucidation of such free energy barriers provides a better understanding of the role of the enzyme in the ECM and is important in the design of future MMP inhibitors.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Chemistry
Subjects:	Q Science > QD Chemistry
Publisher:	Taylor & Francis
ISSN:	0739-1102
Funders:	Biotechnology and Biological Sciences Research Council
Date of First Compliant Deposit:	17 May 2016
Date of Acceptance:	9 February 2016
Last Modified:	05 May 2023 18:19
URI:	https://orca.cardiff.ac.uk/id/eprint/90949

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