Title: Refinement of under-determined loops of Human Prion Protein by database-derived distance constraints

Authors: Feng Cui, Kriti Mukhopadhyay, Won-Bin Young, Robert L. Jernigan, Zhijun Wu

Addresses: Program on Bioinformatics and Computational Biology, Iowa State University, Ames, Iowa 50011, USA. ' Department of Mathematics, Iowa State University, Ames, Iowa 50011, USA. ' NewLink Genetics Inc., University Research Park, Ames, Iowa 50010, USA. ' Program on Bioinformatics and Computational Biology, Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA. ' Program on Bioinformatics and Computational Biology, Department of Mathematics, Iowa State University, Ames, Iowa 50011, USA

Abstract: 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.

Keywords: protein structure refinement; NMR structure determination; database-derived distance constraints; prion structure refinement; under-determined loops; human prion protein; bioinformatics.

DOI: 10.1504/IJDMB.2009.029206

International Journal of Data Mining and Bioinformatics, 2009 Vol.3 No.4, pp.454 - 468

Published online: 09 Nov 2009 *

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