A Survey on π-π Stackings and π-Cations in Prion Protein Structures

Zhang, Jiapu

doi:10.4172/2167-0501.1000e175

Cited by 3 publications

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“…At the same time we found other important π-π stackings such as F175-Y218 and π-cations such as F141-R208, F198-R156, and H155-R136 (Table 4). We can see around the β2-α2 loop there is a "π-chain/circle" Y128-F175-Y218-Y163-F175-Y169-R164-Y128(-Y162) as reported in (Zhang, 2015a(Zhang, & 2015b (where another "π-chain" R208-Y141-Y150-Y157-F198-H187 covering H1 is also reported). By the way, we found the "Cα-distance" to calculate π-cations of George Priya Doss et al ( 2013) is not a perfect way for calculations (Table 4).…”

Section: Bufprp Is Stable Under Neutral-or Low-ph Environments At Roo...supporting

confidence: 60%

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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Section: Bufprp Is Stable Under Neutral-or Low-ph Environments At Roo...supporting

confidence: 60%

Molecular dynamics studies on the buffalo prion protein

Zhang¹,

Wang

Chatterjee

2015

Journal of Biomolecular Structure and Dynamics

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“…5, we may know at S2-H2 loop and its contacts with the C-terminal end of H3 there are the following ππ-stacks Y169-F175, F175-Y218, Y163-Y218, and the following π-cations R164-Y169, R164-Y128, which clearly contribute to the clearly and highly ordered S2-H2 loop structures [65]. For buffaloPrP, we found another two π-stackings: Y163-F175-Y128 [65,66]. Thus, for PrPs, we found an interesting "π-circle" Y128-F175-Y218-Y163-F175-Y169-R164-Y128(-Y162) around the S2-H2 loop.…”

Section: The Hybrid Idea and Some Hybrid Optimization Methodsmentioning

confidence: 99%

The Hybrid Idea of (Energy Minimization) Optimization Methods Applied to Study PrionProtein Structures Focusing on the beta2-alpha2 Loop

Zhang¹

2015

Biochem Pharmacol (Los Angel)

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In molecular mechanics, current generation potential energy functions provide a reasonably good compromise between accuracy and effectiveness. This paper firstly reviewed several most commonly used classical potential energy functions and their optimization methods used for energy minimization. To minimize a potential energy function, about 95% efforts are spent on the Lennard-Jones potential of van der Waals interactions; we also give a detailed review on some effective computational optimization methods in the Cambridge Cluster Database to solve the problem of Lennard-Jones clusters. From the reviews, we found the hybrid idea of optimization methods is effective, necessary and efficient for solving the potential energy minimization problem and the Lennard-Jones clusters problem. An application to prion protein structures is then done by the hybrid idea. We focus on the β2-α2 loop of prion protein structures, and we found (i) the species that has the clearly and highly ordered β2-α2 loop usually owns a 3 10 -helix in this loop, (ii) a "π-circle" Y128-F175-Y218-Y163-F175-Y169-R164-Y128(-Y162) is around the β2-α2 loop.

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“…Hence, it appears that misfolding can potentially commence from either of the two isoenergetic but structurally distinct sub-populations, PUF2* and PUF2**. Mutation of the conserved Pro residues (Zhang, 2015) affects the stability of PUF2*, while mutation of the conserved aromatic residues affects the stability of PUF2** (Figure S5). In this way, misfolding of different mutant variants may commence from or proceed via either PUF2* or PUF2**.…”

Section: Misfolding Can Potentially Commence From Multiple Pufsmentioning

confidence: 99%

“…Tyr168 and Tyr217 are strictly conserved, whereas Phe174 is conserved in all but two species (Huang & Caflisch, 2015). The aromatic interactions between Tyr168, Phe174, and Tyr217 are the most conserved aromatic interactions observed in the structures of different mammalian prion proteins (Zhang, 2015). MD simulation studies have suggested that favorable interactions between Tyr168, Phe174, and Tyr217 stabilize the interface of the β2‐α2 loop and the C‐terminal end of α3 (Huang & Caflisch, 2015; Jung Cheng & Daggett, 2014).…”

Section: Introductionmentioning

confidence: 99%

Mutations of evolutionarily conserved aromatic residues suggest that misfolding of the mouse prion protein may commence in multiple ways

Pal,

Udgaonkar

2023

Journal of Neurochemistry

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The misfolding of the mammalian prion protein from its α‐helix rich cellular isoform to its β‐sheet rich infectious isoform is associated with several neurodegenerative diseases. The determination of the structural mechanism by which misfolding commences, still remains an unsolved problem. In the current study, native‐state hydrogen exchange coupled with mass spectrometry has revealed that the N state of the mouse prion protein (moPrP) at pH 4 is in dynamic equilibrium with multiple partially unfolded forms (PUFs) capable of initiating misfolding. Mutation of three evolutionarily conserved aromatic residues, Tyr168, Phe174, and Tyr217 present at the interface of the β2‐α2 loop and the C‐terminal end of α3 in the structured C‐terminal domain of moPrP significantly destabilize the native state (N) of the protein. They also reduce the free energy differences between the N state and two PUFs identified as PUF1 and PUF2**. It is shown that PUF2** in which the β2‐α2 loop and the C‐terminal end of α3 are disordered, has the same stability as the previously identified PUF2*, but to have a very different structure. Misfolding can commence from both PUF1 and PUF2**, as it can from PUF2*. Hence, misfolding can commence and proceed in multiple ways from structurally distinct precursor conformations. The increased extents to which PUF1 and PUF2** are populated at equilibrium in the case of the mutant variants, greatly accelerate their misfolding. The results suggest that the three aromatic residues may have been evolutionarily selected to impede the misfolding of moPrP.

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A Survey on π-π Stackings and π-Cations in Prion Protein Structures

Cited by 3 publications

References 1 publication

Molecular dynamics studies on the buffalo prion protein

Molecular dynamics studies on the buffalo prion protein

The Hybrid Idea of (Energy Minimization) Optimization Methods Applied to Study PrionProtein Structures Focusing on the beta2-alpha2 Loop

Mutations of evolutionarily conserved aromatic residues suggest that misfolding of the mouse prion protein may commence in multiple ways

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