The neurodegenerative disease epidemic raises with the increase of life expectancy in the developed countries. It is an age-related disorder which affects both humans and animals. Prion diseases are a class of rare, fatal and progressive kind of neurodegenerative diseases including an extensive range of clinicopathological phenotypes (Lafon et al. 2018). They are distinctive infectious agents which are assembled from self-propagating multi-chain of misfolded host-encoded prion protein (PrP) (Terry and Wadsworth 2019). The human prion diseases are conventionally categorized based on their clinicopathological spectrum into Creutzfeldt–Jakob disease (as the most common), fatal insomnia, Gerstmann–Sträussler–Scheinker disease, and variably protease-sensitive prionopathy. All categories except for fatal insomnia denote heterogeneous groups comprising several distinct disease phenotypes or subtypes (Rossi et al. 2019; Zheng et al. 2018).
It is acknowledged that the major reasons for these maladies are the posttranslational transformation of the ubiquitous cellular form of the prion protein (HuPrPc) to misfolded pathogenic isoform (HuPrPSc) (Wille and Requena 2018; Wulf et al. 2017). Furthermore, without exhibiting any covalent alterations, they eventually aggregate with a defined structure (Dai et al. 2019; Vallabh et al. 2020). The quest for determining the mechanisms of Human (Hu) familial prion diseases caused by the mutations of prion protein is never-ending. The structural characteristics of PrPSc have not been entirely identified and the research is open to achieve the ultimate insight into its molecular mechanism. The main barrier in this way is the insoluble nature of PrPSc which prevents the use of high-resolution techniques for whole determination of its structure. Thus, a partial structure of PrPSc with a low resolution is available.
It is well-known that HuPrPSc structure is rich in β-strands whereas HuPrPc mainly consists of α-helix in secondary structure conformation. The structures obtained from NMR reveal a C-terminal globular domain from residue 125 to 228 (human numbering) and an N-terminal flexible disordered tail (Poggiolini et al. 2013). The globular domain is composed of three α-helices forming the residues 144–154 helix 1, 173–194 helix 2, and 200–228 helix 3 as well as a very short anti-parallel β-sheet with residues 128–131 b1 and 161–164 b2. Also, a disulphide bond (Cys179–Cys214) connects helices 2 and 3. Regions of helix 2 and 3 play a decisive role in transforming HuPrPc to HuPrPSc (Castle and Gill 2017; Zheng et al. 2018).
The studies revealed that 40 mutation points in the PrP gene coding originate human familial prion diseases. These mutations mostly happen in the protein globular domain (Guo et al. 2012a; Rossetti et al. 2011). The disease mediated by these mutations causes the spontaneous generation of HuPrPSc in the brain. The misfolding kinetics of HuPrP wild type (WT) as well as the stability of partially folded intermediate species such as HuPrPSc precursors are enhanced by the presence of thermodynamic instability in PrPc (Rossetti et al. 2011). Further investigation of the mutated structure of the PrP molecules reveals the role of their misfolding in different types of spontaneous illness in human even without the existence of infection from exogenous sources (Biasini et al. 2008; Jeffrey et al. 2009). Consequently, the instability in PrP mutants also amplifies the likelihood of misfolding which may be ignored from the quality control cellular pathway and multiplied within cell (Doss et al. 2013).
In this study, four prion systems including three pathogenic mutant diseases caused by the mutation of V176G (Ashraf Fadhil Jomah 2016) and E196A (Wu et al. 2020) and I215V (Munoz-Nieto et al. 2013) at codon 129 and a WT (HuPrP) were simulated using MD of 100 ns. The mechanisms causing human familial prion diseases such as CJD and GSS were established. These PrP systems also were investigated for their physicochemical properties such as hydrophobicity, solvent accessibility, and salt bridge. Results on the structural disorder of mutation clusters in the globular HuPrP domain revealed useful insight.