scholarly journals Molecular dynamics simulation of local structural models of PrPSc reveals how codon 129 polymorphism affects propagation of PrPSc

2019 ◽  
Author(s):  
Hiroki Otaki ◽  
Yuzuru Taguchi ◽  
Noriyuki Nishida

AbstractPrions are unconventional pathogen without nucleotide genome and their pathogenic properties are defined by the primary structure and the conformation of the constituent abnormal isoform (PrPSc) of prion protein (PrP). A polymorphic codon 129 of human PrP that is valine (V129) or methionine (M129) is particularly influential on properties of PrPSc, affecting transmission efficiencies and clinicopathological features. However, how the single residue is so influential has not been elucidated because the detailed structures of PrPSc have not been determined yet due to its incompatibility with high-resolution structural analysis. Previously we created an in-register parallel β-sheet local structural model of human PrPSc encompassing residues 107 to 143 that seemed more compatible with V129 than M129, based on knowledge from α-synuclein amyloids and an NMR-based model of the amyloid of Y145Stop mutant of PrP in the literature. Here, we created an M129-compatible local structural model of PrPSc. Severe destabilization of the model by G127V mutation was consistent with the protective effects of V127 polymorphism of human PrP against prions. It was highly sensitive to the length of the hydrophobic side chain of codon 129 and replacement of M129 with leucine or valine destabilized the structures. Interestingly, the U-shaped β-arch which comprises M129 flexibly changed hydrophobic interaction networks inside the β-arch depending on the interactions with the surrounding structures, whereas the previous model with V129 maintained the similar network patterns irrespective of the surroundings. The differences between the two models may explain influences of the codon 129 polymorphism on transmissions and properties of human prions.

2020 ◽  
Vol 117 (24) ◽  
pp. 13490-13498 ◽  
Author(s):  
Andrew D. Geragotelis ◽  
Mona L. Wood ◽  
Hendrik Göddeke ◽  
Liang Hong ◽  
Parker D. Webster ◽  
...  

The voltage-gated Hv1 proton channel is a ubiquitous membrane protein that has roles in a variety of cellular processes, including proton extrusion, pH regulation, production of reactive oxygen species, proliferation of cancer cells, and increased brain damage during ischemic stroke. A crystal structure of an Hv1 construct in a putative closed state has been reported, and structural models for the channel open state have been proposed, but a complete characterization of the Hv1 conformational dynamics under an applied membrane potential has been elusive. We report structural models of the Hv1 voltage-sensing domain (VSD), both in a hyperpolarized state and a depolarized state resulting from voltage-dependent conformational changes during a 10-μs-timescale atomistic molecular dynamics simulation in an explicit membrane environment. In response to a depolarizing membrane potential, the S4 helix undergoes an outward displacement, leading to changes in the VSD internal salt-bridge network, resulting in a reshaping of the permeation pathway and a significant increase in hydrogen bond connectivity throughout the channel. The total gating charge displacement associated with this transition is consistent with experimental estimates. Molecular docking calculations confirm the proposed mechanism for the inhibitory action of 2-guanidinobenzimidazole (2GBI) derived from electrophysiological measurements and mutagenesis. The depolarized structural model is also consistent with the formation of a metal bridge between residues located in the core of the VSD. Taken together, our results suggest that these structural models are representative of the closed and open states of the Hv1 channel.


2010 ◽  
Vol 5 (9) ◽  
pp. 1934578X1000500
Author(s):  
Iris Stappen ◽  
Joris Höfinghoff ◽  
Gerhard Buchbauer ◽  
Peter Wolschann

Structural modifications of natural (-)-( Z)-β-santalol have shown that the sandalwood odor impression is highly sensitive, even to small structural changes. Particularly, the substitution of the quaternary carbon is of great influence on the scent. Epi-compounds with side chains in the endo-position possess sandalwood odor in only a few derivatives, whereas modifications at this side chain, as well as modification at the bicyclic ring systems mostly lead to a complete loss of sandalwood fragrance.


1997 ◽  
Vol 6 (2) ◽  
pp. 355-363 ◽  
Author(s):  
Vladimir A. Daragan ◽  
Elena E. Ilyina ◽  
Cynthia G. Fields ◽  
Gregg B. Fields ◽  
Kevin H. Mayo

2019 ◽  
Author(s):  
Theresia Gutmann ◽  
Ingmar Schäfer ◽  
Chetan Poojari ◽  
Beate Brankatschk ◽  
Ilpo Vattulainen ◽  
...  

AbstractGlucose homeostasis and growth essentially depend on the peptide hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand–receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have only resolved site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we determined the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin–site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis enabling a comprehensive description of ligand–receptor interactions that ultimately will inform new approaches to structure-based drug design.In briefA cryo-EM structure of the complete insulin receptor ectodomain saturated with four insulin ligands is reported. The structural model of the insulin–insulin receptor complex adopts a T-shaped conformation, reveals two additional insulin-binding sites potentially involved in the initial interaction of insulin with its receptor, and resolves the membrane proximal region.


Author(s):  
Todorova N.Yu.

Purpose. The purpose of the research is to define structural, semantic and grammatical features of the Phraseological Units (PhU) with the component denoting weapon in the English language. It is realized through determining the corpus of PhUs with the component denoting weapon in English, developing their semantic-grammatical classification and describing their most productive structural models in each semantic-grammatical category.Methods. The study is characterized by the integrated application of general and specific research methods. General scientific methods analysis and synthesis, induction and deduction, logical operations definition and classification were used for empirical data processing. As to research methods specific for linguistics, the descriptive method allowed to comprehensively represent the results, the method of internal interpretation was involved in the process of dividing the collected data into semantic-grammatical classes. Within the structural approach, the method of immediate constituents was applied for building structural models of PhUs. The elements of the quantitative analysis ensured the objectivity and accuracy of the obtained results.Results. Defining the notion weapon made it possible to establish the criteria for data collection. The corpus of the analyzed data includes the English PhUs with the component denoting the general concept of weapon (arms, weapon), defensive weapon, cold weapon, fire weapon, their constructive parts and service ammunition. According to the semantic-grammatical classification, the PhUs fall into semantic-grammatical classes: verbal, substantive, adverbial and adjective PhUs, within which the verbal class is the most widespread. In each semantic-grammatical class, the most productive structural models are determined and the type of syntactic connection between the components of the models is described. Verbal PhUs with the component denoting weapon are mainly subordinate phrases formed according to the model V+N. The highest number of substantive PhUs are phrases with an attributive relation between the core and the dependent components (Adj+N). The most typical structural model of adverbial PhUs is Prep+N+N. Adjective PhUs are often comparative phrases with a comparative component in their structure (Adj+Conj+N).Conclusions. The corpus of English PhUs with the component denoting weapon is formed by the PhUs with the component denoting the general concept of weapon, types of weapons, their parts and service ammunition. According to the structural-semantic classification, the analyzed PhUs are divided into structural-semantic classes: verbal, substantive, adverbial and adjective PhUs, among which the verbal class is dominating. The most productive structural model for verbal PhUs is V+N, for substantive PhUs – Adj+N, for adverbial PhUs – Prep+N+N, and for adjective PhUs – Adj+Conj+N.Key words: classification, classes, structural models, verbal idioms, substantive idioms, adverbial idioms, attributive idioms. Мета. Метою дослідження є висвітлення структурних та семантико-граматичних характеристик фразеологічних одиниць (ФО) з компонентом на позначення зброї в англійській мові, досягнення якої уможливлюється шляхом встановлення корпусу ФО з компонентом на позначення зброї в англійській мові, розробки їх семантико-граматичної класифікації та опису найпро-дуктивніших структурних моделей кожного семантико-граматичного розряду.Методи. Дослідження характеризується комплексним застосуванням загальнонаукових та спеціальних лінгвістичних методів. Для обробки емпіричного матеріалу використовувалися загальнонаукові методи аналіз і синтез, індукція та дедукція, логічні операції визначення та класифікація. Серед лінгвістичних методів описовий метод дає змогу репрезентувати результа-ти, а прийом внутрішньої інтерпретації залучався для розподілу ФО за семантико-граматичними розрядами. У межах струк-турного підходу методика безпосередніх складників використовувалась для побудови структурних моделей ФО. Елементи кількісного аналізу забезпечили об’єктивність і точність отриманих результатів.Результати. Окреслення поняття зброя уможливило встановлення корпусу досліджуваних одиниць, до якого ввійшли англійські ФО, в структурі яких є лексема-компонент на позначення узагальненого поняття зброя (arms, weapon), на позначен-ня захисної, метальної, холодної, вогнепальної зброї, її конструктивних частин та боєприпасів. У результаті розробки семан-тико-граматичної класифікації ФО розподілено за семантико-граматичними розрядами: дієслівні, субстантивні, адвербіальні й ад’єктивні ФО, серед яких дієслівні ФО набувають найвищої кількісної представленості. У межах кожного розряду виявлено найпродуктивніші структурні моделі утворення ФО, описано тип синтаксичного зв’язку між компонентами моделей. Дієслівні ФО з компонентом на позначення зброї переважно є підрядними словосполученнями утвореними за моделлю V+N. Найви-ща кількість субстантивних ФО є словосполученнями з атрибутивний зв’язком між стрижневим і залежним компонентом (Adj+N). Найтиповішою моделлю утворення адвербіальних ФО є модель Prep+N+N. Ад’єктивні ФО часто є компаративними словосполученнями із порівняльним компонентом у своїй структурі (Adj+Conj+N).Висновки. Корпус ФО з компонентом на позначення зброї формують ФО з лексемою-компонентом на позначення узагаль-неного поняття зброя, різновидів зброї, її частин та боєприпасів. Згідно зі структурно-семантичною класифікацією ФО роз-падаються на структурно-семантичні розряди: дієслівні, субстантивні, адвербіальні й ад’єктивні ФО, серед яких дієслівні ФО кількісно переважають. Найпродуктивнішою структурною моделлю дієслівних ФО є модель V+N, субстантивних – Adj+N, адвербіальних – Prep+N+N, ад’єктивних – Adj+Conj+N.Ключові слова: класифікація, розряди, структурні моделі, дієслівні фразеологізми, субстантивні фразеологізми, адвербі-альні фразеологізми, атрибутивні фразеологізми.


Author(s):  
Michael Rose

Piezoceramic Patches are commonly used as actuator devices in smart structures if the induced forces are sufficient for the application. To model these devices in a structural dynamics simulation, a finite element model can be augmented by active layers. This needs a suitable element meshing, taking care of the actual shapes and positions of the active patches in use. If many different setups have to be evaluated, which is naturally the case for placement strategies for suitable actuator positions, this approach is quite cumbersome. To ease and speed up the augmentation of fixed finite element models with piezoceramic patches, so called modal correction methods have been successfully used in this context. These approximative methods avoid the remeshing and the reassembling of the underlying finite element model by adapting the modal description of the structural model with the mass, stiffness and electrical coupling effects of the applied patches. In this paper different aspects of this modelling approach are discussed especially for a tool chain to optimize patch locations in an ASAC simulation environment.


2016 ◽  
Vol 03 (02) ◽  
pp. 1650011
Author(s):  
Amelie Hüttner ◽  
Matthias Scherer

We consider the valuation of single name CDS options (CDSO) and related optionalities, particularly extension risk, in the structural default model introduced by Chen and Kou (2009). This jump-diffusion based model is able to generate realistic dynamics for CDS spreads and has decent calibration performance. Due to the European character of the considered options, they can be valued with an efficient Monte Carlo algorithm based on Brownian bridges, adapted from Ruf and Scherer (2011). In contrast to the intensity approach, structural models offer a link to the equity side of a firm’s capital structure, possibly enabling to hedge CDS options with instruments other than CDS.


Author(s):  
Carrie A. Voycheck ◽  
Patrick J. McMahon ◽  
Richard E. Debski

Glenohumeral dislocation is a significant clinical problem and often results in injury to the anteroinferior (anterior band of the inferior glenohumeral ligament (AB-IGHL) and axillary pouch) glenohumeral capsule. [1] However, clinical exams to diagnose capsular injuries are not reliable [2] and poor patient outcome still exists following repair procedures. [3] Validated finite element models of the glenohumeral capsule may be able to improve diagnostic and repair techniques; however, improving the accuracy of these models requires adequate constitutive models to describe capsule behavior. The collagen fibers in the anteroinferior capsule are randomly oriented [4], thus the material behavior of the glenohumeral capsule has been described using isotropic models. [5,6] A structural model consisting of an isotropic matrix embedded with randomly aligned collagen fibers proved to better predict the complex capsule behavior than an isotropic phenomenological model [7] indicating that structural models may improve the accuracy of finite element models of the glenohumeral joint. Many structural models make the affine assumption (local fiber kinematics follow global tissue deformation) however an approach to account for non-affine fiber kinematics in structural models has been recently developed [8]. Evaluating the affine assumption for the capsule would aid in developing an adequate constitutive model. Therefore, the objective of this work was to assess the affine assumption of fiber kinematics in the anteroinferior glenohumeral capsule by comparing experimentally measured preferred fiber directions to the affine-predicted fiber directions.


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