Effects of the pathological E200K mutation on human prion protein: A computational screening and molecular dynamics approach.

The human prion protein gene (PRNP) is mapped to the short arm of chromosome 20 (20pter-12). Prion disease is associated with mutations in the prion protein-encoding gene sequence. Earlier studies found that the mutation G127V in the PRNP increases protein stability. In contrast, the mutation E200K, which has the highest mutation rate in the prion protein, causes Creutzfeldt-Jakob disease (CJD) in humans and induces protein aggregation. We aimed to identify the structural mechanisms of E200k and G127V mutations causing CJD. We used a variety of bioinformatic algorithms, including SIFT, PolyPhen, I-Mutant, PhD-SNP, and SNP& GO, to predict the association of the E200K mutation with prion disease. MD simulation is performed, and graphs for root mean square deviation, root mean square fluctuation, radius of gyration, DSSP, principal component analysis, porcupine, and free energy landscape are generated to confirm and prove the stability of the wild-type and mutant protein structures. The protein is analyzed for aggregation, and the results indicate more fluctuations in the protein structure during the simulation owing to the E200K mutation; however, the G127V mutation makes the protein structure stable against aggregation during the simulation.

A computational study on acetaminophen drug complexed with Mn+, Fe2+, Co+, Ni2+, and Cu+ ions: structural analysis, electronic properties, and solvent effects.

In the present research, the cation-π interactions in acetaminophen-M complexes (M = Mn+, Fe2+, Co+, Ni2+, and Cu+) are investigated using density functional theory (DFT/ωB97XD) in the gas phase and solution. The results show that the absolute values of energy are reduced in going from the gas phase to the solution. Based on the obtained data, the complexes in water are the most stable. The natural bond orbital (NBO) and the atoms in molecules (AIM) analyses are also applied to achieve more details about the nature of interactions. These results are useful for understanding the role of the drug-receptor interactions in the complexes. According to AIM outcomes, the cation-π interactions are the closed-shell and may indicate the partially covalent nature in the complexes. A comprehensive analysis is also performed on the conceptual DFT parameters of the complexes to evaluate their electronic properties. Our findings show increasing the stability and decreasing the reactivity of the complexes in the solution phase with respect to the gas phase. These interactions are ubiquitous in biological systems, and their importance in theoretical models led us to study such important interactions. The results of this study may be useful for the design and synthesis of a variety of supramolecular complexes with the desired properties.

The effect of Saliva officinalis extract on the menopausal symptoms in postmenopausal women: An RCT.

BACKGROUND: The menopausal symptoms are the most common problems in postmenopausal women. Due to the side effects of hormone replacement therapy, the use of medicinal herbs has increased for the treatment of menopausal symptoms. OBJECTIVE: The aim of this study was to evaluate the effect of Saliva officinalis on the decreasing of the severity of the menopausal symptoms in postmenopausal women. MATERIALS AND METHODS: The study was performed on 30 postmenopausal women aged 46-58 yr referred to the healthcare center of Darab who experienced various degrees of postmenopausal symptoms. The severity of menopausal symptoms is recorded by a Menopause Rating Scale. Participants received a 100 mg capsule of sage extract daily for 4 wk. The severity of postmenopausal symptoms was compared before and after four weeks of the consumption of sage extract. RESULTS: The results showed the severity of hot flashes, night sweats, panic, fatigue, and concentration had significant differences before and after the consumption of sage extract. CONCLUSION: It was concluded that Saliva officinalis were effective to change the severity of some of the menopausal symptoms in postmenopausal women.

Atomic insight into prion disorder: An intricate detail gained by 0.5 µs molecular dynamics simulation of preventive G127V and deleterious D178V mutation in prion protein.

In this study we are looking into two contradicting mutations found in prion protein (PrP) viz G127V and D178V, that are reportedly protective and pathogenic, respectively. Despite significant advances in comprehension of the role of pathogenic mutations, the role of protective mutation in amyloid fold inhibition still lacks a substantial basis. To understand the structural basis of protective mutation, molecular dynamics simulation coupled with protein-protein docking and molecular mechanics/Poisson-Boltzmann surface area analysis was used to understand the instant structural variability brought about by these mutations alone and in combination on PrP and prion-prion complex. Atomic-scale investigations successfully revealed that the binding pattern of prion-prion varies differentially in protective and pathogenic mutations with secondary structure showing distinct contrasting patterns, which could supposedly be a critical factor for differential prion behavior in protective and pathogenic mutations. Considering the reported role of an amyloid fold in prion-prion binding, the contrasting pattern has given us a lead in comprehending the role of these mutations and has been used in this study to look for small molecules that can inhibit amyloid fold for prion-prion interaction in pathogenic mutant carrying PrP.

Complications of nonionizing radiofrequency on divided attention.

Exposure to electromagnetic fields is considered as a potential hazard for biological systems. The objective of our investigation is the study of probable consequences of radiofrequency electromagnetic fields from Wi-Fi router devices on the short-term memory, and attention's levels. A population consisting of 312 female college students (14 to 17 years old) was elected by cluster random sampling. Teenagers were divided into two groups of control group (Wi-Fi nonusers; n = 138), and experiment group (Wi-Fi users; n = 174). Both groups have been examined using short-term memory tests; selective attention, and also divided attention tests. According to the results, there was no significant difference between using Wi-Fi router devices on levels of selective attentions and short-term memory of the sample students with the control group. However, analyses revealed that there is a significant correlation between the use of Wi-Fi routers and declining levels of divided attentions. Our investigation has demonstrated the adverse consequences of 2.4-2.48 GHz radiofrequency electromagnetic fields of Wi-Fi router devices on divided attention levels of female university students that should be mentioned as a technological risk factor and taken into account by healthcare organizations.

D224V and S128Y mutation in FSHRED influence thumb movement differentially: An intricate insight gained by short-term molecular dynamics simulation.

Follicle-stimulating hormone-follicle-stimulating hormone receptor (FSH-FSHR) interaction is one of the most thoroughly studied signaling pathways primarily because of being implicated in sexual reproduction in mammals by way of maintaining gonadal function and sexual fertility. Despite material advances in understanding the role of point mutations, their mechanistic basis in FSH-FSHR signaling is still confined to mystically altered behavior of sTYS335 (sulfated tyrosine) yet lacking a substantial theory. To understand the structural basis of receptor modulation, we choose two behaviorally contradicting mutations, namely S128Y (activating) and D224Y (inactivating), found in FSH receptor responsible for ovarian hyperstimulation syndrome and ovarian dysgenesis, respectively. Using short-term molecular dynamics simulations, the atomic scale investigations reveal that the binding pattern of sTYS with FSH and movement of the thumb region of FSHR show distinct contrasting patterns in the two mutants, which supposedly could be a critical factor for differential FSHR behavior in activating and inactivating mutations.

Structural discordance in HIV-1 Vpu from brain isolate alarms amyloid fibril forming behavior- a computational perspective.

HIV-1 being the most widespread type worldwide, its accounts for almost 95% of all infections including HIV associated dementia (HAD) that triggers neurological dysfunction and neurodegeneration in patients. The common features associated with HAD and other neurodegenerative diseases are accumulation of amyloid plaques, neuronal loss and deterioration of cognitive abilities, amongst which amyloid fibrillation is considered to be a hallmark. The success of effective therapeutics lies in the understanding of mechanisms leading to neurotoxicity. Few viral proteins like gp-120 are known to be involved in aggregation and enhancement of viral infectivity while comprehending the neurotoxic role of some other proteins is still underway. In the current study, amyloidogenic potential of HIV-1 Vpu protein from brain isolate is investigated through computational approaches. The aggregation propensity of brain derived HIV-1 Vpu was assessed by several amyloid prediction servers that projected the region 4-35 to be amyloidogenic. The protein structure was modeled and subjected to 70 ns molecular dynamics (MD) simulation to investigate the transformation of α-helical conformation of the predicted aggregate region into ß-sheet, proposing the protein's ability to initiate fibril formation that is central to amyloidogenic proteins. The structural features of brain derived HIV-1 Vpu were consistent with the in silico amyloid prediction results that depicts the conformational change in the region 8-28 of which residues Ala8, Ile9, Val10, Ala19, Ile20 and Val21 constitutes ß-sheet formation. The α-helix/ß-sheet discordance of the predicted region was reflected in the simulation study highlighting the possible structural transition associated with HIV-1 Vpu protein of brain isolate.

Sequence-dependent dynamical instability of the human prion protein: a comparative simulation study.

The present study aimed to explore the most probable regions of the human prion protein backbone for which the initial steps of conformational transitions as a result of intrinsic and extrinsic perturbing factors on the protein structure can be assigned. A total of 0.3-µs molecular dynamics simulations on several analog structures of the protein have been performed. To mimic the impact of the extrinsic and intrinsic destructive parameters on the dynamical characteristics of the protein, mild acidic conditions and R208H mutation have been simulated. The findings indicated that distribution of conformational flexibilities along the protein chain was almost independent of the induced perturbing factors, and was mostly centralized on certain distinct parts of the structure comprising residues 132-145 and 187-203. Analyses also revealed that the segment comprising residues 187-203 may be considered as a peptide sequence, possessing high potential to start the initial steps of conformational rearrangements due to the induced physicochemical alterations. Sequence alignment and molecular dynamics data also revealed that segment 178-203 prefers to accommodate in extended structures rather than α-helices. Region 178-203 may be considered as a peptide switch capable of initiating the conformational transitions due to the introduced modifications and perturbing parameters.

Spectrophotometric determination of L-cysteine by using polyvinylpyrrolidone-stabilized silver nanoparticles in the presence of barium ions.

In this article a simple and selective colorimetric probe for cysteine determination using silver nano particles (AgNPS) is described. The determination process was based upon the surface plasmon resonance properties of polyvinylpyrrolidone-stabilized AgNPS. Interaction of AgNPS with cysteine molecules in the presence of barium ions induced a red shift in the surface plasmon resonance (SPR) maximum of AgNPs, as a result of nanoparticle aggregation. Consequently, yellow color of AgNP solution was changed to pink. The linear range for the determination of cysteine was 3.2-8.2 µM (R=0.9965) with a limit of detection equal to 2.8 µM (3σ). The proposed method was successfully applied to the determination of cysteine in human plasma samples. Acceptable recovery results of the spiked samples confirmed the validity of the proposed method.

Conformational instability of human prion protein upon residue modification: a molecular dynamics simulation study.

Technical strategies like amino acid substitution and residue modification have been widely used to characterize the importance of key amino acids and the role that each residue plays in the structural and functional properties of protein molecules. However, there is no systematic approach to assess the impact of the substituted/modified amino acids on the conformational dynamics of proteins. In this investigation to clarify the effects of residue modifications on the structural dynamics of human prion protein (PrP), a comparative molecular dynamics simulation study on the native and the amino acid-substituted analog at position 208 of PrP has been performed. It is believed that Arginine to Histidine mutation at position 208 is responsible for the structural transition of the native form of human prion protein to the pathogenic isoform causing Creutzfeldt-Jakob disease (CJD). So, three 10 ns molecular dynamics simulations on three model constructs have been performed. Simulation results indicated considerable differences of conformational fluctuations for Alanine substituted construct (PrPALA) and the analog form (PrPSB) comprising the neutralized state of the Arginine residue at position 208 of the human prion protein. According to our data, substitution of the Arginine residue by the uncharged state of this residue induces some reversible structural alterations in the intrinsically flexible loop area including residues 167-171 of PrP. Thus, deprotonation of Arg(208) is a weak perturbation to the structural fluctuations of the protein backbone and the resulting construct behaves almost identical as its native form. Otherwise, Alanine substitution at position 208 imposed an irreversible impact on the secondary and tertiary structure of the protein, which leads to conformational instabilities in the remote hot region comprising residues 190-195 of the C-terminal part of helix 2. Based on the results, it could be deduced that the observed conformational transitions upon Arg(208) to His point mutation, which is the main reason for CJD, may be mainly related to the structural instabilities due to the induced-conformational changes that caused alterations in local/spatial arrangements of the force distributions in the backbone of the human prion protein.

Conformational changes of a chemically modified HRP: formation of a molten globule like structure at pH 5.

Horseradish peroxidase is an all alpha-helical enzyme, which widely used in biochemistry applications mainly because of its ability to enhance the weak signals of target molecules. This monomeric heme-containing plant peroxidase is also used as a reagent for the organic synthesis, biotransformation, chemiluminescent assays, immunoassays, bioremediation, and treatment of wastewaters as well. Accordingly, enhancing stability and catalytic activity of this protein for biotechnological uses has been one of the important issues in the field of biological investigations in recent years. In this study, pH-induced structural alterations of native (HRP), and modified (MHRP) forms of Horseradish peroxidase have been investigated. Based on the results, dramatic loss of the tertiary structure and also the enzymatic activity for both forms of enzymes recorded at pH values lower than 6 and higher than 8. Ellipticiy measurements, however, indicated very slight variations in the secondary structure for MHRP at pH 5. Spectroscopic analysis also indicated that melting of the tertiary structure of MHRP at pH 5 starts at around 45 °C, which is associated to the pKa of His 42 that has a serious role in keeping of the heme prostethic group in its native position through natural hydrogen bond network in the enzyme structure. According to our data, a molten globule like structure of a chemically modified form of Horseradish peroxidase at pH 5 with initial steps of conformational transition in tertiary structure with almost no changes in the secondary structure has been detected. Despite of some conformational changes in the tertiary structure of MHRP at pH 5, this modified form still keeps its catalytic activity to some extent besides enhanced thermal stability. These findings also indicated that a molten globular state does not necessarily preclude efficient catalytic activity.

Contribution of a putative salt bridge and backbone dynamics in the structural instability of human prion protein upon R208H mutation.

Molecular dynamics simulation method is used to assess the contribution of a disease-associated salt bridge in the early stages of the conformational rearrangement of human prion protein upon Arg208-->His mutation, which causes Creutzfeldt-Jakob disease. Previous investigations have suggested that the breakage of this putative salt bridge (D144/E146<-->Arg208) between helix 1 and helix 3 is responsible for such a mutation-driven process. So far, no experimental data has been reported in order to distinguish the contribution of this single salt bridge in the initial steps of amyloid formation. Consequently, we decided to investigate the role of this salt bridge in early conformational rearrangements. To remove the salt bridge without perturbations in the backbone structure, the neutralized states of the involved residues were used. Three 10-ns molecular dynamics simulations on three initial structures have been performed. The results revealed that the early stages of the conformational rearrangements, against common belief, are mainly associated with the mutation-induced global changes in the backbone dynamics but not with the breaking of the salt bridge.