COMPARING FOLDING MECHANISMS OF DIFFERENT PRION PROTEINS BY Gō MODEL

2013 ◽  
Vol 12 (08) ◽  
pp. 1341004
Author(s):  
XUE WU ◽  
TING FU ◽  
ZHI-LONG XIU ◽  
LIU YIN ◽  
JIN-GUANG WANG ◽  
...  
Keyword(s):  
Free Energy ◽  
Prion Protein ◽  
Energy Barrier ◽  
Prion Proteins ◽  
Coarse Grained ◽  
Transmissible Spongiform Encephalopathies ◽  
Free Energy Barrier ◽  
Spongiform Encephalopathies ◽  
Go Model ◽  
Folding Free Energy

Prions are associated with neurodegenerative diseases induced by transmissible spongiform encephalopathies. The infectious scrapie form is referred to as PrP Sc , which has conformational change from normal prion with predominant α-helical conformation to the abnormal PrP Sc that is rich in β-sheet content. Neurodegenerative diseases have been found from both human and bovine sources, but there are no reports about infected by transmissible spongiform encephalopathies from rabbit, canine and horse sources. Here we used coarse-grained Gō model to compare the difference among human, bovine, rabbit, canine, and horse normal (cellular) prion proteins. The denatured state of normal prion has relation with the conversion from normal to abnormal prion protein, so we used all-atom Gō model to investigate the folding pathway and energy landscape for human prion protein. Through using coarse-grained Gō model, the cooperativity of the five prion proteins was characterized in terms of calorimetric criterion, sigmoidal transition, and free-energy profile. The rabbit and horse prion proteins have higher folding free-energy barrier and cooperativity, and canine prion protein has slightly higher folding free-energy barrier comparing with human and bovine prion proteins. The results from all-atom Gō model confirmed the validity of C α-Gō model. The correlations of our results with previous experimental and theoretical researches were discussed.

scholarly journals On the folding of a structurally complex protein to its metastable active state

2018 ◽  
Vol 115 (9) ◽  
pp. 1998-2003 ◽  
Author(s):  
V. V. Hemanth Giri Rao ◽  
Shachi Gosavi
Keyword(s):  
Free Energy ◽  
Energy Barrier ◽  
Coarse Grained ◽  
Structural Basis ◽  
Free Energy Barrier ◽  
Active Conformation ◽  
Protease Inhibition ◽  
Stable Conformation ◽  
Folding Simulations ◽  
And Function

For successful protease inhibition, the reactive center loop (RCL) of the two-domain serine protease inhibitor, α1-antitrypsin (α1-AT), needs to remain exposed in a metastable active conformation. The α1-AT RCL is sequestered in a β-sheet in the stable latent conformation. Thus, to be functional, α1-AT must always fold to a metastable conformation while avoiding folding to a stable conformation. We explore the structural basis of this choice using folding simulations of coarse-grained structure-based models of the two α1-AT conformations. Our simulations capture the key features of folding experiments performed on both conformations. The simulations also show that the free energy barrier to fold to the latent conformation is much larger than the barrier to fold to the active conformation. An entropically stabilized on-pathway intermediate lowers the barrier for folding to the active conformation. In this intermediate, the RCL is in an exposed configuration, and only one of the two α1-AT domains is folded. In contrast, early conversion of the RCL into a β-strand increases the coupling between the two α1-AT domains in the transition state and creates a larger barrier for folding to the latent conformation. Thus, unlike what happens in several proteins, where separate regions promote folding and function, the structure of the RCL, formed early during folding, determines both the conformational and the functional fate of α1-AT. Further, the short 12-residue RCL modulates the free energy barrier and the folding cooperativity of the large 370-residue α1-AT. Finally, we suggest experiments to test the predicted folding mechanism for the latent state.

scholarly journals Structure analysis of human Prion protein involved in Sporadic Fatal Insomnia

2018 ◽  
Author(s):  
Philip J Camp ◽  
Pardis Tabaee Damavandi ◽  
Richard W Pickersgill ◽  
Martin T Dove
Keyword(s):  
Prion Protein ◽  
Prion Proteins ◽  
Transmissible Spongiform Encephalopathies ◽  
Human Form ◽  
Native Form ◽  
Spongiform Encephalopathies ◽  
Root Cause ◽  
Progressive Neurodegeneration ◽  
Human Prion Protein ◽  
Key Residues

AbstractPrion disorders are the root cause of Transmissible Spongiform Encephalopathies (TSE), a group of lethal diseases portrayed by progressive neurodegeneration and spongiosis. In recent years, researchers have come to understand that it is not the endogenous presence of Prions itself that causes neurodegeneration, but the amount of prion proteins that accumulates in the nervous tissue, leading them to exert neurotoxicity. More specifically, the cause of these disorders is mapped to several mutations that can bring the prion protein structure to a disordered permanent misfolded state. Our research is focused on Sporadic Fatal Insomnia (sFI), a rare TSE characterized by severe and chronic insomnia, leading to a life expectancy estimation of about two and a half years, from the onset of the first symptoms. The goal of this work was to analyze through computational studies the structure of the native human Prion Protein (PrPnat) and compare it with the toxic form (FI-Prion) which causes disease. Our findings show that the structure of the human mutant FI-Prion, responsible for Sporadic Fatal Insomnia is more flexible than the native human form PrPnat. Specific regions of the mutant seem to fluctuate more freely than the corresponding loops in the native form. We also identified amino acids Tyr128 and Met129 to be the key residues playing a major role in the manifestation of the disease. Therefore, we’ve learnt that the FI-Prion is more flexible than PrPnat. In addition, we also confirmed that sporadic fatal insomnia is undoubtedly an infectious disease.

scholarly journals Structure analysis of human Prion protein involved in Sporadic Fatal Insomnia

2019 ◽  
Author(s):  
Pardis Tabaee Damavandi
Keyword(s):  
Prion Protein ◽  
Prion Proteins ◽  
Transmissible Spongiform Encephalopathies ◽  
Human Form ◽  
Native Form ◽  
Spongiform Encephalopathies ◽  
Root Cause ◽  
Progressive Neurodegeneration ◽  
Human Prion Protein ◽  
Key Residues

Prion disorders are the root cause of Transmissible Spongiform Encephalopathies (TSE), a group of lethal diseases portrayed by progressive neurodegeneration and spongiosis. In recent years, researchers have come to understand that it is not the endogenous presence of Prions itself that causes neurodegeneration, but the amount of prion proteins that accumulates in the nervous tissue, leading them to exert neurotoxicity. More specifically, the cause of these disorders is mapped to several mutations that can bring the prion protein structure to a disordered permanent misfolded state. Our research is focused on Sporadic Fatal Insomnia (sFI), a rare TSE characterized by severe and chronic insomnia, leading to a life expectancy estimation of about two and a half years, from the onset of the first symptoms. The goal of this work was to analyze through computational studies the structure of the native human Prion Protein (PrPnat) and compare it with the toxic form (FI-Prion) which causes disease. Our findings show that the structure of the human mutant FI-Prion, responsible for Sporadic Fatal Insomnia is more flexible than the native human form PrPnat. Specific regions of the mutant seem to fluctuate more freely than the corresponding loops in the native form. We also identified amino acids Tyr128 and Met129 to be the key residues playing a major role in the manifestation of the disease. Therefore, we’ve learnt that the FI-Prion is more flexible than PrPnat. In addition, we also confirmed that sporadic fatal insomnia is undoubtedly an infectious disease.

scholarly journals The fast-folding HP35 double mutant has a substantially reduced primary folding free energy barrier

2008 ◽  
Vol 129 (15) ◽  
pp. 155104 ◽  
Author(s):  
Hongxing Lei ◽  
Xiaojian Deng ◽  
Zhixiang Wang ◽  
Yong Duan
Keyword(s):  
Free Energy ◽  
Energy Barrier ◽  
Double Mutant ◽  
Free Energy Barrier ◽  
Folding Free Energy

A MODEL FOR SOLVENT MEDIATED INTERACTIONS BETWEEN MOLECULES AND SURFACES

2009 ◽  
Vol 20 (05) ◽  
pp. 747-759
Author(s):  
JUAN G. DIAZ OCHOA
Keyword(s):  
Game Theory ◽  
Free Energy ◽  
Molecular Recognition ◽  
Adsorption Energy ◽  
Energy Barrier ◽  
Energy Landscape ◽  
Explicit Representation ◽  
Coarse Grained ◽  
Free Energy Barrier ◽  
Coarse Grained Model

This work introduces a novel coarse-grained model representing the dynamics of polar molecules that adsorb on a substrate in the presence of a solvent. The motivation of the model is to avoid the explicit representation of the solvent. Instead, the solvent-mediated interaction is indirectly represented using a fluctuating energy landscape. The dynamics, on which this model is based, are similar to the dynamics in game theory. In particular, the strategy of an agent in a game is similar to the modification of the free energy barrier between the molecule and the substrate induced by other companion molecules. The aim of this method is to show how the interplay between solvents and companion molecules can imply a modification in the adsorption energy of molecules, and how this modification can buffer the adsorption of specific molecules on surfaces. The results, and their implications in the molecular recognition of surfaces, are discussed.

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

DFT study on the hydrolysis of metsulfuron-methyl: A sulfonylurea herbicide

2018 ◽  
Vol 17 (08) ◽  
pp. 1850050 ◽  
Author(s):  
Qiuhan Luo ◽  
Gang Li ◽  
Junping Xiao ◽  
Chunhui Yin ◽  
Yahui He ◽  
...  
Keyword(s):  
Free Energy ◽  
Water Molecule ◽  
Carbonyl Group ◽  
Energy Barrier ◽  
Density Functional ◽  
Free Energy Barrier ◽  
Functional Theory ◽  
Metsulfuron Methyl ◽  
Catalytic Role ◽  
Hydrolysis Of

Sulfonylureas are an important group of herbicides widely used for a range of weeds and grasses control particularly in cereals. However, some of them tend to persist for years in environments. Hydrolysis is the primary pathway for their degradation. To understand the hydrolysis behavior of sulfonylurea herbicides, the hydrolysis mechanism of metsulfuron-methyl, a typical sulfonylurea, was investigated using density functional theory (DFT) at the B3LYP/6-31[Formula: see text]G(d,p) level. The hydrolysis of metsulfuron-methyl resembles nucleophilic substitution by a water molecule attacking the carbonyl group from aryl side (pathway a) or from heterocycle side (pathway b). In the direct hydrolysis, the carbonyl group is directly attacked by one water molecule to form benzene sulfonamide or heterocyclic amine; the free energy barrier is about 52–58[Formula: see text]kcal[Formula: see text]mol[Formula: see text]. In the autocatalytic hydrolysis, with the second water molecule acting as a catalyst, the free energy barrier, which is about 43–45[Formula: see text]kcal[Formula: see text]mol[Formula: see text], is remarkably reduced by about 11[Formula: see text]kcal[Formula: see text]mol[Formula: see text]. It is obvious that water molecules play a significant catalytic role during the hydrolysis of sulfonylureas.

scholarly journals Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease‐associated T183A variant

2021 ◽  
Vol 15 (1) ◽  
pp. 193-196
Author(s):  
Máximo Sanz-Hernández ◽  
Alfonso De Simone
Keyword(s):  
Prion Protein ◽  
Nmr Assignments ◽  
Chemical Shifts ◽  
Prion Diseases ◽  
Random Coil ◽  
Transmissible Spongiform Encephalopathies ◽  
Globular Domain ◽  
Structural Elements ◽  
Spongiform Encephalopathies ◽  
Human Prion Protein

AbstractTransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of the human prion protein (huPrP). Despite efforts into investigating the process of huPrP aggregation, the mechanisms triggering its misfolding remain elusive. A number of TSE-associated mutations of huPrP have been identified, but their role at the onset and progression of prion diseases is unclear. Here we report the NMR assignments of the C-terminal globular domain of the wild type huPrP and the pathological mutant T183A. The differences in chemical shifts between the two variants reveal conformational alterations in some structural elements of the mutant, whereas the analyses of secondary shifts and random coil index provide indications on the putative mechanisms of misfolding of T183A huPrP.

scholarly journals Efficient Conversion of Normal Prion Protein (PrP) by Abnormal Hamster PrP Is Determined by Homology at Amino Acid Residue 155

2001 ◽  
Vol 75 (10) ◽  
pp. 4673-4680 ◽  
Author(s):  
Suzette A. Priola ◽  
Joëlle Chabry ◽  
Kaman Chan
Keyword(s):  
Amino Acid ◽  
Prion Protein ◽  
Amino Acid Residue ◽  
Animal Species ◽  
Alpha Helix ◽  
Proteinase K ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
A Cell ◽  
Resistant Product

ABSTRACT In the transmissible spongiform encephalopathies, disease is closely associated with the conversion of the normal proteinase K-sensitive host prion protein (PrP-sen) to the abnormal proteinase K-resistant form (PrP-res). Amino acid sequence homology between PrP-res and PrP-sen is important in the formation of new PrP-res and thus in the efficient transmission of infectivity across species barriers. It was previously shown that the generation of mouse PrP-res was strongly influenced by homology between PrP-sen and PrP-res at amino acid residue 138, a residue located in a region of loop structure common to PrP molecules from many different species. In order to determine if homology at residue 138 also affected the formation of PrP-res in a different animal species, we assayed the ability of hamster PrP-res to convert a panel of recombinant PrP-sen molecules to protease-resistant PrP in a cell-free conversion system. Homology at amino acid residue 138 was not critical for the formation of protease-resistant hamster PrP. Rather, homology between PrP-sen and hamster PrP-res at amino acid residue 155 determined the efficiency of formation of a protease-resistant product induced by hamster PrP-res. Structurally, residue 155 resides in a turn at the end of the first alpha helix in hamster PrP-sen; this feature is not present in mouse PrP-sen. Thus, our data suggest that PrP-res molecules isolated from scrapie-infected brains of different animal species have different PrP-sen structural requirements for the efficient formation of protease-resistant PrP.

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