{"data":{"id":"10.6084/m9.figshare.c.2091347.v1","type":"dois","attributes":{"doi":"10.6084/m9.figshare.c.2091347.v1","prefix":"10.6084","suffix":"m9.figshare.c.2091347.v1","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Hezekiel M. Kumalo","affiliation":[],"nameIdentifiers":[]},{"name":"Soumendranath Bhakat","affiliation":[],"nameIdentifiers":[]},{"name":"Soliman, Mahmoud E.","nameType":"Personal","givenName":"Mahmoud E.","familyName":"Soliman","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"Investigation of flap flexibility of β-secretase using molecular dynamic simulations"}],"publisher":"Figshare","container":{},"publicationYear":2015,"subjects":[{"subject":"Biophysics"},{"subject":"Biochemistry"},{"subject":"Molecular Biology"},{"subject":"Pharmacology"},{"subject":"Biotechnology"},{"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":"Sociology"},{"subject":"FOS: Sociology","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Sociology","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"69999 Biological Sciences not elsewhere classified","subjectScheme":"FOR"},{"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":"Computational Biology"}],"contributors":[],"dates":[{"date":"2015-12-05","dateType":"Created"},{"date":"2016-05-20","dateType":"Updated"},{"date":"2015","dateType":"Issued"}],"language":null,"types":{"ris":"GEN","bibtex":"misc","citeproc":"article","schemaOrg":"Collection","resourceType":"Collection","resourceTypeGeneral":"Collection"},"relatedIdentifiers":[{"relationType":"IsSupplementTo","relatedIdentifier":"10.1080/07391102.2015.1064831","relatedIdentifierType":"DOI"},{"relationType":"IsIdenticalTo","relatedIdentifier":"10.6084/m9.figshare.c.2091347","relatedIdentifierType":"DOI"}],"relatedItems":[],"sizes":[],"formats":[],"version":null,"rightsList":[{"rights":"CC-BY","rightsUri":"http://creativecommons.org/licenses/by/3.0/us"}],"descriptions":[{"description":"Flap motif and its dynamics were extensively reported in aspartate proteases, e.g. HIV proteases and plasmepsins. Herein, we report the first account of flap dynamics amongst different conformations of β-secretase using molecular dynamics simulation. Various parameters were proposed and a selected few were picked which could appropriately describe the flap motion. Three systems were studied, namely Free (BACE\u003csub\u003eFree\u003c/sub\u003e) and two ligand-bound conformations, which belonged to space groups P6\u003csub\u003e1\u003c/sub\u003e22 (BACE\u003csub\u003eBound1\u003c/sub\u003e) and C222\u003csub\u003e1\u003c/sub\u003e (BACE\u003csub\u003eBound2\u003c/sub\u003e), respectively and four parameters (distance between the flaps tip residue, Thr72 and Ser325, \u003ci\u003ed\u003c/i\u003e\u003csub\u003e1\u003c/sub\u003e; dihedral angle, \u003ci\u003eϕ\u003c/i\u003e (Thr72-Asp32-Asp228-Ser325); TriCα angles, \u003ci\u003eθ\u003c/i\u003e\u003csub\u003e1\u003c/sub\u003e (Thr72-Asp32-Ser325), and \u003ci\u003eθ\u003c/i\u003e\u003csub\u003e2\u003c/sub\u003e (Thr72-Asp228-Ser325)) were proposed to understand the change in dynamics of flap domain and the extent of flap opening and closing. Analysis of, \u003ci\u003eθ\u003c/i\u003e\u003csub\u003e2\u003c/sub\u003e, \u003ci\u003ed\u003c/i\u003e\u003csub\u003e1\u003c/sub\u003e, \u003ci\u003eθ\u003c/i\u003e\u003csub\u003e1\u003c/sub\u003e and \u003ci\u003eϕ\u003c/i\u003e confirmed that the BACE\u003csub\u003eFree\u003c/sub\u003e adopted semi-open, open and closed conformations with slight twisting during flap opening. However, BACE\u003csub\u003eBound1\u003c/sub\u003e (P6122) showed an adaptation to open conformation due to lack of hydrogen bond interaction between the ligand and flap tip residue. A slight flap \u003ci\u003etwisting, ϕ\u003c/i\u003e (\u003ci\u003elateral twisting\u003c/i\u003e) was observed for BACE\u003csub\u003eBound1\u003c/sub\u003e during flap opening which correlates with the opening of BACE\u003csub\u003eFree\u003c/sub\u003e. Contradictory to the BACE\u003csub\u003eBound1\u003c/sub\u003e, the BACE\u003csub\u003eBound2\u003c/sub\u003e locked the flap in a closed conformation throughout the simulation due to formation of a stable hydrogen bond interaction between the flap tip residue and ligand. Analyses of all three systems highlight that \u003ci\u003ed\u003c/i\u003e\u003csub\u003e1\u003c/sub\u003e, \u003ci\u003eθ\u003c/i\u003e\u003csub\u003e2\u003c/sub\u003e and \u003ci\u003eϕ\u003c/i\u003e can be precisely used to describe the extent of flap opening and closing concurrently with snapshots along the molecular dynamics trajectory across several conformations of β-secretase.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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