Prion protein conversion triggered by acidic condition: a molecular dynamics study through different force fields

Abstract

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 PrPSc, 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.

Elevated temperatures accelerate the formation of toxic amyloid fibrils of hen egg‐white lysozyme

“…This was identical to the results using molecular dynamics simulation techniques that elevating temperature could accelerate the unfolding process of prion protein and increase the β ‐sheet structures (Chamachi & Chakrabarty, 2017; Chen et al., 2013). Our data were also in accordance with the molecular dynamics simulation results that the structural conversion of cellular prion protein was triggered by acidic pH (Lu et al., 2013; Thompson et al., 2018).…”

“…The surfactants like sarkosyl in solution of pH 9.0 (Khan et al., 2018) and sodium dodecyl benzenesulfonate in solution of pH 7.4 (Khan et al., 2019), and food colouring agent like Allura red in solution of pH 7.0 (Al‐Shabib et al., 2019) can also promote the formation of HEWL fibrils. Like HEWL protein, prion protein can form into amyloid fibrils under acidic pH conditions demonstrated both by experimental studies (Hornemann & Glockshuber, 1998; Singh & Udgaonkar, 2016) and molecular dynamics simulation techniques (Thompson et al., 2018). Elevated temperatures can accelerate the unfolding process and increase the β ‐sheet structures of prion protein using molecular dynamics simulation techniques (Chen et al., 2013; Gu et al., 2003).…”

Mutation-Dependent Refolding of Prion Protein Unveils Amyloidogenic-Related Structural Ramifications: Insights from Molecular Dynamics Simulations

“…Such an elongated structure is a novel indicator of misfolding and drove the conformational conversion of PrP C to PrP Sc , critical information needed for understanding the molecular pathogenesis of prion diseases. Furthermore, Thompson et al 66 performed molecular dynamics simulations using a set of force fields to study the molecular basis of PrP C misfolding followed by conformational conversion and found that only GROMOS96 53a6 and AMBER99SB force fields are capable of capturing the crucial elongated β-sheet structure during refolding. Moreover, another study also found a discrepancy in protein force fields in replicating the experimental state populations.…”