Molecular Dynamics Simulations Capture the Misfolding of the Bovine Prion Protein at Acidic pH

Cheng, Chin Jung; Daggett, Valerie

doi:10.3390/biom4010181

Cited by 25 publications

(33 citation statements)

References 74 publications

(112 reference statements)

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“…In this procedure, they determined the critical role of additionally generated β-strands in the conversion of PrP C structures through computational analysis. The salt bridge region between the 147th aspartate and 151st arginine residue was disrupted; this event did not critically alter the structural stability of D147N PrP Additionally, they observed conformational variation in the full-length bovine PrP prion at low pH using molecular dynamics [53]. The conformational variation of native full-length bovine PrP prion structures was found to be PrP Sc with additional generation of β-strands; the role of the Met-129 residue was determined by conformational and secondary structure analysis, as shown in Figure 13.…”

Section: From Prpmentioning

confidence: 99%

Structure-Property Relationship of Amyloidogenic Prion Nanofibrils

Lee¹,

Choi²,

Kim³

et al. 2017

Prion - An Overview

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The structure and its property for the prion nanofibrils, which exhibit self-assembled steric zipper, amyloid fibrils, are described in this chapter. There is the belief of origin for the infectiousness of the prion can be its molecular structure. It is due to the amyloid toxicity, which is related to its beta sheet rich molecular structure and self-aggregated long fibrils. There is evidence that the difference between PrP c and PrP sc is transitioned beta sheet from alpha helix to self-assemble and then to the amyloidogenic fibrils. Therefore, the scope of this chapter is the amyloidogenic structural characteristics of prion fibrils and its relationship to the property. The molecular structural characteristics can be changed by properties such as affinity, toxicity, infectivity, and so on, so this is a key factor to understand the origin of prion disease and develop the therapeutic strategy. One of the main properties of amyloid fibrils that we want to describe here is mechanical property such as dynamic property and material property for prion nanofibrils. This chapter can shed light on understanding the infectious characteristics of prion and the relationship of its molecular structures.

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Section: From Prpmentioning

confidence: 99%

Structure-Property Relationship of Amyloidogenic Prion Nanofibrils

Lee¹,

Choi²,

Kim³

et al. 2017

Prion - An Overview

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“…In PDB Bank (www.rcsb.org), bovine PrP has the following PDB entries: 1DWY.pdb, 1DWZ.pdb, 1DX0.pdb, 1DX1.pdb, and 1SKH.pdb, etc. In the PubMed on 'bovine prion protein molecular dynamics', we found 1DWY.pdb [Ahn & Son, 2007, Cheng, 2014, 1DWZ.pbb [Herrmann, Gntert, & Wüthrich, 2002], 1DX0.pdb [Kunze et al, 2008] were used. 1DWZ.pdb has 20 structures and, by clustering the 20 structures, we picked up the Number 9 from these 20 structures and we superposed it to 1DWY.pdb and found their RMSD (Root Mean Square Deviation) value is 0 Å (however if we superposed it to 1DX0.pdb, the RMSD is 1.22117 Å).…”

Section: Homology Structure For Bufprp C (124-227)mentioning

confidence: 99%

“…1DWZ.pdb has 20 structures and, by clustering the 20 structures, we picked up the Number 9 from these 20 structures and we superposed it to 1DWY.pdb and found their RMSD (Root Mean Square Deviation) value is 0 Å (however if we superposed it to 1DX0.pdb, the RMSD is 1.22117 Å). Thus, we also chose 1DWY.pdb as [Cheng, 2014] (at the same time in order to conveniently make comparisons with the results of bovine PrP in [Cheng, 2014]). The BufPrP(124-227) homology model used in this paper was constructed by one mutation S143N at position 143 using the NMR structure 1DWY.pdb of Bovine PrP(124-227) (where the experimental temperature is 293 K, pH value is 4.5, and pressure is 1 ATM, etc).…”

Section: Homology Structure For Bufprp C (124-227)mentioning

confidence: 99%

“…The mutation H187R will make the SB HIS187-ARG156 (N-O) broken. • For bovine PrP C , at low pH, hydrophobic contacts with M129 nucleated the nonnative β-strand, and at mid-pH, polar contacts involving Q168 and D178 facilitated the formation of a hairpin at the flexible N-terminus [Cheng, 2014]. For BufPrP C , we found there is a HYD between MET129 and LEU130 with occupied rate 100% whether under low or neutral pH environments, and there is a HB Y169-D178 instead of the polar contact Q168-D178 of bovine PrP C .…”

Section: Some Special Contributions To the Stable Bufprpmentioning

confidence: 99%

“…For BufPrP C , we found there is a HYD between MET129 and LEU130 with occupied rate 100% whether under low or neutral pH environments, and there is a HB Y169-D178 instead of the polar contact Q168-D178 of bovine PrP C . At ASP178, there exists SB ASP178-ARG164 and SB ASP178-HIS177, and one polar contact ASP178-ARG164 (where polar contact is defined including both HBs and SBs formed between residues/atoms as in [Cheng, 2014]). …”

Section: Some Special Contributions To the Stable Bufprpmentioning

confidence: 99%

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Molecular dynamics studies on the buffalo prion protein

Zhang¹,

Wang

Chatterjee

2015

Journal of Biomolecular Structure and Dynamics

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It was reported that buffalo is a low susceptibility species resisting to transmissible spongiform encephalopathies (TSEs) (same as rabbits, horses, and dogs). TSEs, also called prion diseases, are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of species (except for rabbits, dogs, horses, and buffalo), manifesting as scrapie in sheep and goats; bovine spongiform encephalopathy (BSE or "mad-cow" disease) in cattle; chronic wasting disease in deer and elk; and Creutzfeldt-Jakob diseases, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, and Kulu in humans etc. In molecular structures, these neurodegenerative diseases are caused by the conversion from a soluble normal cellular prion protein (PrP(C)), predominantly with α-helices, into insoluble abnormally folded infectious prions (PrP(Sc)), rich in β-sheets. In this article, we studied the molecular structure and structural dynamics of buffalo PrP(C) (BufPrP(C)), in order to understand the reason why buffalo is resistant to prion diseases. We first did molecular modeling of a homology structure constructed by one mutation at residue 143 from the NMR structure of bovine and cattle PrP(124-227); immediately we found that for BufPrP(C)(124-227), there are five hydrogen bonds (HBs) at Asn143, but at this position, bovine/cattle do not have such HBs. Same as that of rabbits, dogs, or horses, our molecular dynamics studies also revealed there is a strong salt bridge (SB) ASP178-ARG164 (O-N) keeping the β2-α2 loop linked in buffalo. We also found there is a very strong HB SER170-TYR218 linking this loop with the C-terminal end of α-helix H3. Other information, such as (i) there is a very strong SB HIS187-ARG156 (N-O) linking α-helices H2 and H1 (if mutation H187R is made at position 187, then the hydrophobic core of PrP(C) will be exposed (L.H. Zhong (2010). Exposure of hydrophobic core in human prion protein pathogenic mutant H187R. Journal of Biomolecular Structure and Dynamics 28(3), 355-361)), (ii) at D178, there is a HB Y169-D178 and a polar contact R164-D178 for BufPrP(C) instead of a polar contact Q168-D178 for bovine PrP(C) (C.J. Cheng, & V. Daggett. (2014). Molecular dynamics simulations capture the misfolding of the bovine prion protein at acidic pH. Biomolecules 4(1), 181-201), (iii) BufPrP(C) owns three 310 helices at 125-127, 152-156, and in the β2-α2 loop, respectively, and (iv) in the β2-α2 loop, there is a strong π-π stacking and a strong π-cation F175-Y169-R164.(N)NH2, has been discovered.

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Computational insights into pH‐dependence of structure and dynamics of pyrazinamidase: A comparison of wild type and mutants

Esmaeeli

Mehrnejad

Mir-Derikvand

et al. 2018

J of Cellular Biochemistry

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The mycobacterial enzyme pyrazinamidase (PZase) is the target of key tuberculosis drug, pyrazinamide. Mutations in PZase cause drug resistance. Herein, three point mutations, W68G, L85P, and V155G, were investigated through over 8 µs of molecular dynamics simulations coupled with essential dynamics and binding pocket analysis at neutral (pH = 7) and acidic (pH = 4) ambient conditions. The 51‐71 flap region exhibited drastic displacement leading to enlargement of binding cavity, especially at the lower pH. Accessibility of solvent to the active site of the mutant enzymes was also reduced. The protonation of key surface residues at low pH results in more contribution of these residues to structural stability and integrity of the enzyme and reduced interactions with solvent molecules, which acts as a cage, keeping the enzyme together. The observed results suggest a pattern of structural alterations due to point mutations in PZase, which is consistent with other experimental and theoretical investigations and, can be harnessed for drug design purposes.

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Molecular Dynamics Simulations Capture the Misfolding of the Bovine Prion Protein at Acidic pH

Cited by 25 publications

References 74 publications

Structure-Property Relationship of Amyloidogenic Prion Nanofibrils

Structure-Property Relationship of Amyloidogenic Prion Nanofibrils

Molecular dynamics studies on the buffalo prion protein

Computational insights into pH‐dependence of structure and dynamics of pyrazinamidase: A comparison of wild type and mutants

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