{"data":{"id":"10.6084/m9.figshare.c.2343256.v1","type":"dois","attributes":{"doi":"10.6084/m9.figshare.c.2343256.v1","prefix":"10.6084","suffix":"m9.figshare.c.2343256.v1","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Nash, Anthony","nameType":"Personal","givenName":"Anthony","familyName":"Nash","affiliation":[],"nameIdentifiers":[]},{"name":"Birch, Helen L.","nameType":"Personal","givenName":"Helen L.","familyName":"Birch","affiliation":[],"nameIdentifiers":[]},{"name":"Leeuw, Nora H. De","nameType":"Personal","givenName":"Nora H. De","familyName":"Leeuw","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"Mapping intermolecular interactions and active site conformations: from human MMP-1 crystal structure to molecular dynamics free energy calculations"}],"publisher":"Figshare","container":{},"publicationYear":2016,"subjects":[{"subject":"Biophysics"},{"subject":"Biochemistry"},{"subject":"29999 Physical Sciences not elsewhere classified","subjectScheme":"FOR"},{"subject":"FOS: Physical sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Physical sciences","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Medicine"},{"subject":"Physiology"},{"subject":"FOS: Biological sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Biological sciences","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"39999 Chemical Sciences not elsewhere classified","subjectScheme":"FOR"},{"subject":"FOS: Chemical sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Chemical sciences","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"69999 Biological Sciences not elsewhere classified","subjectScheme":"FOR"},{"subject":"Computational Biology"}],"contributors":[],"dates":[{"date":"2016-02-17","dateType":"Created"},{"date":"2016-04-25","dateType":"Updated"},{"date":"2016","dateType":"Issued"}],"language":null,"types":{"ris":"GEN","bibtex":"misc","citeproc":"article","schemaOrg":"Collection","resourceType":"Collection","resourceTypeGeneral":"Collection"},"relatedIdentifiers":[],"relatedItems":[],"sizes":[],"formats":[],"version":null,"rightsList":[{"rights":"CC-BY","rightsUri":"http://creativecommons.org/licenses/by/3.0/us"}],"descriptions":[{"description":"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.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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