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Prion protein conversion triggered by acidic condition: a molecular dynamics study through different force fields
Author(s) -
Thompson Helen Nathalia,
Thompson Claudia Elizabeth,
Andrade Caceres Rafael,
Dardenne Laurent Emmanuel,
Netz Paulo Augusto,
Stassen Hubert
Publication year - 2018
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.25380
Subject(s) - bovine spongiform encephalopathy , prion protein , molecular dynamics , gene isoform , chemistry , biophysics , force field (fiction) , in silico , helix (gastropod) , biochemistry , computational chemistry , biology , physics , medicine , ecology , disease , pathology , quantum mechanics , snail , gene
Prions are proteins that cause a group of invariably fatal neurodegenerative diseases, one of the most known being bovine spongiform encephalopathy. The three‐dimensional structure of PrP Sc , the altered isoform of the prion protein, has not been fully elucidated yet, and studies on prion conversion mechanisms must rely on hypothetical β‐rich structures. Experimental and computational studies indicate that the use of low pH is capable to produce a gain of β‐structure content in the otherwise unstructured N‐terminal region. These in silico studies have used different PrP fragments from distinct organisms, and with different lengths and simulation protocols, making it difficult to identify the influence of the force fields on the formation of such structures. Here, we performed a systematic study of the influence of six well‐established force fields (GROMOS96 53a6, GROMOS96 43a1, AMBER99SB, AMBER99SB‐ILDN, CHARMM27, and OPLS‐AA/L) on the process of structural conversion of the Syrian hamster cellular prion protein simulated at acidic and neutral pH. From our analysis, we observe a strong dependence of the results with the different force fields employed. Additionally, only GROMOS96 53A6 and AMBER99SB force fields are capable to capture a high β‐sheet formation at acidic pH and adequately reproduce the neutral pH. In both cases, the β‐sheet elongation seems to be guided by the movement of the N‐terminal tail toward the N‐terminal of α‐helix HB under acidic condition. These results comprise the most wide‐ranging study to date correlating force fields to structural changes in the cellular prion protein. © 2018 Wiley Periodicals, Inc.