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Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Understanding the basis for protective role of E219K prion variant using Molecular Dynamics Simulations

The scrapie form of prion protein is responsible for various neurodegenerative diseases. Mutation in prion protein is one of the factors which leads to pathogenic conversion of normal prion PrPc protein to scrapie form PrPSc [Friedman-Levi et al. (2011)]. But, previous studies on the prion protein also suggest that E219K prion mutant (glutamate to Lysine mutation at residue position 219) is more stable than the wild type protein [Biljan et al. (2012), Jahandideh et al. (2015)]. Hence, in this study the wild type prion protein, prion mutant E200K (glutamate to Lysine mutation at residue position 200) and E219K, a naturally occurring mutant, which is considered to protect against Creutzfeldt-Jakob disease (CJD) have been studied. In order to understand the structural changes, we have carried out detailed atomistic simulation of three systems. Principal component analysis, free energy analysis, dynamic cross correlation analysis, and other analyses have been carried out. Our analysis shows that the extra stability of E219K mutant is result of increase in number of native contacts, strong hydrogen bond network and less random motions. The pathogenicity of E200K may be the result of loss of some crucial salt-bridge interaction and anti-correlated motion between helix 2(H2) and helix 3 (H3) and increase in solvent accessible surface area of hydrophobic residues. Thus this study shows that native contacts, salt-bridge interaction and hydrogen bonds between H2 and H3 plays important role in the maintaining stability/pathogenicity of the prion protein.

References
    Y. Friedman-Levi et al. (2011). Fatal prion disease in a mouse model of genetic E200K Creutzfeldt-Jakob disease. PLoS pathogens, 7(11), e1002350

    I. Biljan, G. Giachin, G. Ilc, I. Zhukov, J. Plavec, & G. Legname. (2012). Structural basis for the protective effect of the human prion protein carrying the dominant-negative E219K polymorphism. Biochem. J., 446(2), 243-251

    S. Jahandideh, M. Jamalan, & M. Faridounnia. (2015) Molecular dynamics study of the dominant-negative E219K polymorphism in human prion protein. J. Biomol. Struct. Dyn., 33(6), 1315-1325.



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Vinod Jani*,
Uddhavesh Sonavane
and Rajendra Joshi*

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Currently working as Principal Technical Officer in the HPC-M&BA Group at Centre for Development of Advanced Computing (C-DAC), Pune, India in the areas of molecular modelling under the guidance of Dr. Rajendra Joshi and Dr. Uddhavesh Sonavane, Vinod Jani will present a short oral from the platform.

High Performance Computing-Medical & Bioinformatics Application Group,
Centre for Development of Advanced computing (C-DAC),
C-DAC Innovation Park,
Panchavati, Pashan,
Pune 411007, India

Email: vinodj@cdac.in
rajendra@cdac.in