Campus Units

Biochemistry, Biophysics and Molecular Biology, Roy J. Carver Department of, Mathematics, Bioinformatics and Computational Biology

Document Type

Article

Publication Version

Accepted Manuscript

Publication Date

2009

Journal or Book Title

International journal of data mining and bioinformatics

Volume

3

Issue

4

First Page

454

Last Page

468

DOI

10.1504/IJDMB.2009.029206

Abstract

Computational simulations of the conversion from the normal cellular prion (PrPc) to the scrapie prion (PrPSc) are usually based on the structures determined by NMR because of the difficulties in crystallizing prion protein. Due to insufficient experimental restraints, a biologically critical loop region in PrPc (residues 167–171), which is a potential binding site for Protein X, is under-determined in most mammalian species. Here, we show that by adding information about distance constraints derived from a database of high-resolution protein structures, this under-determined loop as well as other secondary structural elements of the E200K variant of human prion protein (hPrPc), a disease-related isoform, can be refined into more realistic structures in the structural ensemble with improved quality and increased accuracy. In particular, the ensemble becomes more compact after the refinement and the percentage of residues in the most favourable region of the Ramachandran diagram is increased to about 90% in the refined structures from the 80 to 85% range in the previously reported structures. Our results not only provide significantly improved structures of the prion protein and hence would facilitate insights into its conversion in the spongiform encephalopathies, but also demonstrate the strong potential for using databases of known protein structures for structure determination and refinement.

Comments

This is a manuscript of an article published as Cui, Feng, Kriti Mukhopadhyay, Won-Bin Young, Robert L. Jernigan, and Zhijun Wu. "Refinement of under-determined loops of Human Prion Protein by database-derived distance constraints." International journal of data mining and bioinformatics 3, no. 4 (2009): 454-468. doi: 10.1504/IJDMB.2009.029206. Posted with permission.

Copyright Owner

Inderscience Enterprises Ltd.

Language

en

File Format

application/pdf

Published Version

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