scholarly journals Divergence Entropy-Based Evaluation of Hydrophobic Core in Aggressive and Resistant Forms of Transthyretin

Entropy ◽  
2021 ◽  
Vol 23 (4) ◽  
pp. 458
Author(s):  
Mateusz Banach ◽  
Katarzyna Stapor ◽  
Piotr Fabian ◽  
Leszek Konieczny ◽  
Irena Roterman
Keyword(s):  
Tertiary Structure ◽  
Early Stage ◽  
Intermediate Stage ◽  
Transformation Process ◽  
Hydrophobic Core ◽  
Spherical Micelle ◽  
Globular Structure ◽  
Folding Process ◽  
Decisive Importance ◽  
The Status

The two forms of transthyretin differing slightly in the tertiary structure, despite the presence of five mutations, show radically different properties in terms of susceptibility to the amyloid transformation process. These two forms of transthyretin are the object of analysis. The search for the sources of these differences was carried out by means of a comparative analysis of the structure of these molecules in their native and early intermediate stage forms in the folding process. The criterion for assessing the degree of similarity and differences is the status of the hydrophobic core. The comparison of the level of arrangement of the hydrophobic core and its initial stages is possible thanks to the application of divergence entropy for the early intermediate stage and for the final forms. It was shown that the minimal differences observed in the structure of the hydrophobic core of the forms available in PDB, turned out to be significantly different in the early stage (ES) structure in folding process. The determined values of divergence entropy for both ES forms indicate the presence of the seed of hydrophobic core only in the form resistant to amyloid transformation. In the form of aggressively undergoing amyloid transformation, the structure lacking such a seed is revealed, being a stretched one with a high content of β-type structure. In the discussed case, the active presence of water in the structural transformation of proteins expressed in the fuzzy oil drop model (FOD) is of decisive importance for the generation of the final protein structure. It has been shown that the resistant form tends to generate a centric hydrophobic core with the possibility of creating a globular structure, i.e. a spherical micelle-like form. The aggressively transforming form reveals in the structure of its early intermediate, a tendency to form the ribbon-like micelle as observed in amyloid.

scholarly journals The Structure of Amyloid Versus the Structure of Globular Proteins

2020 ◽  
Vol 21 (13) ◽  
pp. 4683 ◽  
Author(s):  
Piotr Fabian ◽  
Mateusz Banach ◽  
Katarzyna Stapor ◽  
Leszek Konieczny ◽  
Magdalena Ptak-Kaczor ◽  
...  
Keyword(s):  
Gaussian Distribution ◽  
Experimental Studies ◽  
Data Bank ◽  
Globular Proteins ◽  
Hydrophobic Core ◽  
Single Chain ◽  
Spherical Micelle ◽  
Globular Structure ◽  
A Chain ◽  
High Level

The issue of changing the structure of globular proteins into an amyloid form is in the focus of researchers' attention. Numerous experimental studies are carried out, and mathematical models to define the essence of amyloid transformation are sought. The present work focuses on the issue of the hydrophobic core structure in amyloids. The form of ordering the hydrophobic core in globular proteins is described by a 3D Gaussian distribution analog to the distribution of hydrophobicity in a spherical micelle. Amyloid fibril is a ribbon-like micelle made up of numerous individual chains, each representing a flat structure. The distribution of hydrophobicity within a single chain included in the fibril describes the 2D Gaussian distribution. Such a description expresses the location of polar residues on a circle with a center with a high level of hydrophobicity. The presence of this type of order in the amyloid forms available in Preotin Data Bank (PDB) (both in proto- and superfibrils) is demonstrated in the present work. In this system, it can be assumed that the amyloid transformation is a chain transition from 3D Gauss ordering to 2D Gauss ordering. This means changing the globular structure to a ribbon-like structure. This observation can provide a simple mathematical model for simulating the amyloid transformation of proteins.

scholarly journals Downhill, Ultrafast and Fast Folding Proteins Revised

2020 ◽  
Vol 21 (20) ◽  
pp. 7632
Author(s):  
Mateusz Banach ◽  
Katarzyna Stapor ◽  
Leszek Konieczny ◽  
Piotr Fabian ◽  
Irena Roterman
Keyword(s):  
Amino Acids ◽  
Protein Folding ◽  
Gaussian Function ◽  
Water Environment ◽  
Mutual Arrangement ◽  
Hydrophobic Core ◽  
Spherical Micelle ◽  
Native Form ◽  
Hydrophobic Residues ◽  
Folding Process

Research on the protein folding problem differentiates the protein folding process with respect to the duration of this process. The current structure encoded in sequence dogma seems to be clearly justified, especially in the case of proteins referred to as fast-folding, ultra-fast-folding or downhill. In the present work, an attempt to determine the characteristics of this group of proteins using fuzzy oil drop model is undertaken. According to the fuzzy oil drop model, a protein is a specific micelle composed of bi-polar molecules such as amino acids. Protein folding is regarded as a spherical micelle formation process. The presence of covalent peptide bonds between amino acids eliminates the possibility of free mutual arrangement of neighbors. An example would be the construction of co-micelles composed of more than one type of bipolar molecules. In the case of fast folding proteins, the amino acid sequence represents the optimal bipolarity system to generate a spherical micelle. In order to achieve the native form, it is enough to have an external force field provided by the water environment which directs the folding process towards the generation of a centric hydrophobic core. The influence of the external field can be expressed using the 3D Gaussian function which is a mathematical model of the folding process orientation towards the concentration of hydrophobic residues in the center with polar residues exposed on the surface. The set of proteins under study reveals a hydrophobicity distribution compatible with a 3D Gaussian distribution, taken as representing an idealized micelle-like distribution. The structure of the present hydrophobic core is also discussed in relation to the distribution of hydrophobic residues in a partially unfolded form.

scholarly journals Model of Early Stage Intermediate in Respect to Its Final Structure

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 866 ◽  
Author(s):  
Piotr Fabian ◽  
Katarzyna Stapor ◽  
Irena Roterman
Keyword(s):  
Protein Folding ◽  
Contingency Table ◽  
Polypeptide Chain ◽  
Early Stage ◽  
Probability Distributions ◽  
Hydrophobic Core ◽  
Structural Form ◽  
The Status ◽  
The Relationship ◽  
Structural Code

The model, describing a method of determining the structure of an early intermediate in the process of protein folding to analyze nonredundant PDB protein bases, allows determining the relationship between the sequence of tetrapeptides and their structural forms expressed by structural codes. The contingency table expressing such a relationship can be used to predict the structure of polypeptides by proposing a structural form with a precision limited to the structural code. However, by analyzing structural forms in native forms of proteins based on the fuzzy oil drop model, one can also determine the status of polypeptide chain fragments with respect to the assumptions of this model. Whether the probability distributions for both compliant and noncompliant forms were similar or whether the tetrapeptide sequences showed some differences at a level of a set of structural codes was investigated. The analysis presented here indicated that some sequences in both forms revealed differences in probability distributions expressed as a negative statistically significant correlation coefficient. This meant that the identified sections (tetrapeptides) took different forms against the fuzzy oil drop model. It may suggest that the information of the final status with respect to hydrophobic core formation is already carried by the structure of the early-stage intermediate.

scholarly journals Structure of the Hydrophobic Core Determines the 3D Protein Structure—Verification by Single Mutation Proteins

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 767 ◽  
Author(s):  
Mateusz Banach ◽  
Piotr Fabian ◽  
Katarzyna Stapor ◽  
Leszek Konieczny ◽  
and Irena Roterman
Keyword(s):  
Tertiary Structure ◽  
Polypeptide Chain ◽  
De Novo ◽  
Water Environment ◽  
Single Mutation ◽  
Hydrophobic Core ◽  
3D Protein Structure ◽  
Folding Process ◽  
External Force Field ◽  
A Chain

Four de novo proteins differing in single mutation positions, with a chain length of 56 amino acids, represent diverse 3D structures: monomeric 3α and 4β + α folds. The reason for this diversity is seen in the different structure of the hydrophobic core as a result of synergy leading to the generation of a system in which the polypeptide chain as a whole participates. On the basis of the fuzzy oil drop model, where the structure of the hydrophobic core is expressed by means of the hydrophobic distribution function in the form of a 3D Gaussian distribution, it has been shown that the composition of the hydrophobic core in these two structural forms is different. In addition, the use of a model to determine the structure of the early intermediate in the folding process allows to indicate differences in the polypeptide chain geometry, which, combined with the construction of a common hydrophobic nucleus as an effect of specific synergy, may indicate the reason for the diversity of the folding process of the polypeptide chain. The results indicate the need to take into account the presence of an external force field originating from the water environment and that its active impact on the formation of a hydrophobic core whose participation in the stabilization of the tertiary structure is fundamental.

Application of Advanced Technologies in Natural Product Research: A Review with Special Emphasis on ADMET Profiling

2020 ◽  
Vol 21 (10) ◽  
pp. 751-767
Author(s):  
Pobitra Borah ◽  
Sangeeta Hazarika ◽  
Satyendra Deka ◽  
Katharigatta N. Venugopala ◽  
Anroop B. Nair ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Natural Product ◽  
Dynamic Range ◽  
Early Stage ◽  
Attrition Rate ◽  
Drug Candidates ◽  
Advanced Technologies ◽  
Natural Product Research ◽  
The Status ◽  
Safety Parameters

The successful conversion of natural products (NPs) into lead compounds and novel pharmacophores has emboldened the researchers to harness the drug discovery process with a lot more enthusiasm. However, forfeit of bioactive NPs resulting from an overabundance of metabolites and their wide dynamic range have created the bottleneck in NP researches. Similarly, the existence of multidimensional challenges, including the evaluation of pharmacokinetics, pharmacodynamics, and safety parameters, has been a concerning issue. Advancement of technology has brought the evolution of traditional natural product researches into the computer-based assessment exhibiting pretentious remarks about their efficiency in drug discovery. The early attention to the quality of the NPs may reduce the attrition rate of drug candidates by parallel assessment of ADMET profiling. This article reviews the status, challenges, opportunities, and integration of advanced technologies in natural product research. Indeed, emphasis will be laid on the current and futuristic direction towards the application of newer technologies in early-stage ADMET profiling of bioactive moieties from the natural sources. It can be expected that combinatorial approaches in ADMET profiling will fortify the natural product-based drug discovery in the near future.

scholarly journals Chest computed tomography imaging features in patients with coronavirus disease 2019 (COVID-19)

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110106
Author(s):  
Hoda Salah Darwish ◽  
Mohamed Yasser Habash ◽  
Waleed Yasser Habash
Keyword(s):  
Computed Tomography ◽  
Intermediate Phase ◽  
Early Stage ◽  
Lower Lobe ◽  
Ground Glass Opacity ◽  
Intermediate Stage ◽  
Mediastinal Lymphadenopathy ◽  
Imaging Features ◽  
Stage Disease ◽  
Bilateral Lesions

Objective To analyze computed tomography (CT) features of symptomatic patients with coronavirus disease 2019 (COVID-19). Methods Ninety-five symptomatic patients with COVID-19 confirmed by reverse-transcription polymerase chain reaction from 1 May to 14 July 2020 were retrospectively enrolled. Follow-up CT findings and their distributions were analyzed and compared from symptom onset to late-stage disease. Results Among all patients, 15.8% had unilateral lung disease and 84.2% had bilateral disease with slight right lower lobe predilection (47.4%). Regarding lesion density, 49.4% of patients had pure ground glass opacity (GGO) and 50.5% had GGO with consolidation. Typical early-stage patterns were bilateral lesions in 73.6% of patients, diffuse lesions (41.0%), and GGO (65.2%). Pleural effusion occurred in 13.6% and mediastinal lymphadenopathy in 11.5%. During intermediate-stage disease, 47.4% of patients showed GGO as the disease progressed; however, consolidation was the predominant finding (52.6%). Conclusion COVID-19 pneumonia manifested on lung CT scans with bilateral, peripheral, and right lower lobe predominance and was characterized by diffuse bilateral GGO progressing to or coexisting with consolidation within 1 to 3 weeks. The most frequent CT lesion in the early, intermediate, and late phases was GGO. Consolidation appeared in the intermediate phase and gradually increased, ending with reticular and lung fibrosis-like patterns.

scholarly journals Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations

2021 ◽  
Vol 22 (14) ◽  
pp. 7375
Author(s):  
Julie Ledoux ◽  
Alain Trouvé ◽  
Luba Tchertanov
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Tertiary Structure ◽  
Average Distance ◽  
Intrinsic Disorder ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Hydrophobic Core ◽  
Direct Evaluation ◽  
Dynamics Simulations

The kinase insert domain (KID) of RTK KIT is the key recruitment region for downstream signalling proteins. KID, studied by molecular dynamics simulations as a cleaved polypeptide and as a native domain fused to KIT, showed intrinsic disorder represented by a set of heterogeneous conformations. The accurate atomistic models showed that the helical fold of KID is mainly sequence dependent. However, the reduced fold of the native KID suggests that its folding is allosterically controlled by the kinase domain. The tertiary structure of KID represents a compact array of highly variable α- and 310-helices linked by flexible loops playing a principal role in the conformational diversity. The helically folded KID retains a collapsed globule-like shape due to non-covalent interactions associated in a ternary hydrophobic core. The free energy landscapes constructed from first principles—the size, the measure of the average distance between the conformations, the amount of helices and the solvent-accessible surface area—describe the KID disorder through a collection of minima (wells), providing a direct evaluation of conformational ensembles. We found that the cleaved KID simulated with restricted N- and C-ends better reproduces the native KID than the isolated polypeptide. We suggest that a cyclic, generic KID would be best suited for future studies of KID f post-transduction effects.

Reproductive Failure in Populations of the Dog-Whelk, Nucella Lapillus, Caused by Imposex Induced by Tributyltin from Antifouling Paints

1986 ◽  
Vol 66 (4) ◽  
pp. 767-777 ◽  
Author(s):  
P. E. Gibbs ◽  
G. W. Bryan
Keyword(s):  
Vas Deferens ◽  
Early Stage ◽  
Premature Death ◽  
Intermediate Stage ◽  
Reproductive Failure ◽  
Nucella Lapillus ◽  
Egg Capsules ◽  
Male Characters ◽  
High Incidence ◽  
Declining Populations

The development of male characters, notably a penis and a vas deferens, on the female (the phenomenon of ‘imposex’) of the dog-whelk, Nucella lapillus, is described. Three stages are recognized: an ‘early’ stage involving the formation of a vas deferens and a small penis, an ‘intermediate’ stage characterized by the enlargement of the female penis to a size approaching that of the male and a ‘late’ stage during which the female opening (vulva) is occluded by overgrowth of vas deferens tissue. This blockage of the pallial oviduct prevents the release of egg capsules and renders the female sterile. The extent and cause of such reproductive failure is evident from the high incidence of females containing aborted capsules in declining populations close to sources of tributyltin (TBT) contamination. These same populations comprise fewer females than expected and it would appear that the accumulation of aborted capsules within the pallial oviduct eventually causes the premature death of the female.

Site controlling in infrastructure projects by digital methods

2021 ◽  
Author(s):  
Tino Walther ◽  
Marianne Pieper ◽  
Hans-Joachim Bargstädt
Keyword(s):  
Performance Measurement ◽  
Construction Industry ◽  
Process Model ◽  
Current Practice ◽  
Early Stage ◽  
Recommendations For Action ◽  
Digital Planning ◽  
The Status ◽  
Project Controlling ◽  
Digital Methods

<p>The construction industry is essentially determined by digital transformation and an increasingly complex market environment. Project controlling and monitoring is of high importance for construction site activities to achieve the project goals. Digital planning and recording methods make it possible to identify deviations at an early stage and to ensure the profitability of the project. To discuss the current practice of construction performance measurement as well as digital approaches in this domain, a qualitative study was carried out. The results of this empirical analysis examine the status quo of the construction performance measurement in civil engineering companies to illustrate the currently used methods and trends. Findings for the future use of digital planning and recording methods were obtained from the investigation. Based on empirical hypotheses, recommendations for action as well as for an improved process model are given.</p>

scholarly journals A simulation to identify the optimal area to survey in the early stage of invasion by Solenopsis invicta

2021 ◽  
Author(s):  
Shumpei Hisamoto ◽  
Koichi Goka ◽  
Yoshiko Sakamoto
Keyword(s):  
Mathematical Model ◽  
Cost Effectiveness ◽  
Solenopsis Invicta ◽  
Early Stage ◽  
Geographical Information ◽  
Survey Area ◽  
Single Colony ◽  
The Status ◽  
Optimal Area ◽  
The Cost

Abstract Efforts to eradicate invasive alien species commonly use simulations to calculate the cost-effectiveness of surveys. Although eradication of Solenopsis invicta in the early stages of an invasion is important, few simulations are available to calculate the cost-effectiveness of surveys when a single colony has been detected. In the case of S. invicta, it is difficult to determine from the status of the detected colony whether new queens have dispersed, so it is necessary to consider dispersal as a probabilistic event and calculate its probability. We therefore first constructed a mathematical model in which we used Bayesian statistics to estimate the probability of dispersal as a function of the results of the survey. This mathematical model revealed that the efficacy of the survey and the associated cost differed greatly between cases depending on whether dispersal was or was not confirmed. Next, we developed a simulation that incorporated this mathematical model to inform the determination of the survey area when a single colony had been detected. The simulation showed how ecological parameters and geographical information could be used to identify an efficacious survey area, even in heterogeneous landscapes such as international ports where invasions occur sporadically. Finally, we used this simulation to assess the efficacy of a survey in the case of an S. invicta outbreak at the Port of Tokyo, Japan. The results suggested that the survey covered a sufficiently wide area but that it could have been designed in a more efficacious manner.

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