The impact of mutations on the structural and functional properties of SARS-CoV-2 proteins: A comprehensive bioinformatics analysis

AbstractAn in-depth analysis of first wave SARS-CoV-2 genome is required to identify various mutations that significantly affect viral fitness. In the present study, we have performed comprehensive in-silico mutational analysis of 3C-like protease (3CLpro), RNA dependent RNA polymerase (RdRp), and spike (S) proteins with the aim of gaining important insights into first wave virus mutations and their functional and structural impact on SARS-CoV-2 proteins. Our integrated analysis gathered 3465 SARS-CoV-2 sequences and identified 92 mutations in S, 37 in RdRp, and 11 in 3CLpro regions. The impact of those mutations was also investigated using various in silico approaches. Among these 32 mutations in S, 15 in RdRp, and 3 in 3CLpro proteins are found to be deleterious in nature and could alter the structural and functional behavior of the encoded proteins. D614G mutation in spike and P323L in RdRp are the globally dominant variants with a high frequency. Most of them have also been found in the binding moiety of the viral proteins which determine their critical involvement in the host-pathogen interactions and drug targets. The findings of the current study may facilitate better understanding of COVID-19 diagnostics, vaccines, and therapeutics.

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The Impact of Mutations on the Pathogenic and Antigenic Activity of SARS-CoV-2 during the First Wave of the COVID-19 Pandemic: A Comprehensive Immunoinformatics Analysis

Vaccines ◽

10.3390/vaccines9121410 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1410

Author(s):

Zulqarnain Baloch ◽

Aqsa Ikram ◽

Mohamad S. Hakim ◽

Faryal Mehwish Awan

Keyword(s):

In Silico ◽

Drug Targets ◽

Mutational Analysis ◽

Viral Fitness ◽

Integrated Analysis ◽

T Cell Epitopes ◽

Antigenic Activity ◽

Functional Behavior ◽

Depth Analysis ◽

The Impact

An in-depth analysis of first-wave SARS-CoV-2 genome is required to identify various mutations that significantly affect viral fitness. In the present study, we performed a comprehensive in silico mutational analysis of 3C-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), and spike (S) proteins with the aim of gaining important insights into first-wave virus mutations and their functional and structural impact on SARS-CoV-2 proteins. Our integrated analysis gathered 6000 SARS-CoV-2 sequences and identified 92 mutations in S, 37 in RdRp, and 11 in 3CLpro regions. The impact of these mutations was also investigated using various in silico approaches. Among these, 32 mutations in S, 15 in RdRp, and 3 in 3CLpro proteins were found to be deleterious in nature and could alter the structural and functional behavior of the encoded proteins. The D614G mutation in spike and the P323Lmutation in RdRp are the globally dominant variants with a high frequency. Most of the identified mutations were also found in the binding moiety of the viral proteins which determine their critical involvement in host–pathogen interactions and may represent drug targets. Furthermore, potential CD4+ and CD8+ T cell epitopes were predicted, and their overlap with genetic variations was explored. This study also highlights several hot spots in which HLA and drug selective pressure overlap. The findings of the current study may allow a better understanding of COVID-19 diagnostics, vaccines, and therapeutics.

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Prospectus Regulation and Prospectus Liability

10.1093/law/9780198846529.001.0001 ◽

2020 ◽

Keyword(s):

Capital Markets ◽

Integrated Analysis ◽

Securities Litigation ◽

Depth Analysis ◽

Prospectus Liability ◽

Capital Markets Union ◽

The Uk ◽

Rome I ◽

The Impact ◽

The Eu

This book provides integrated analysis of and guidance on the Prospectus Regulation 2017, civil liability for a misleading prospectus, and securities litigation in a European context. The prospectus rules are one of the cornerstones of the EU Capital Markets Union and analysis of this aspect of harmonisation, the areas not covered by the rules, and the impact of Brexit, provides valuable reference for all advising and researching this field. The book discusses the subjects of Prospectus Regulation from both a legal and economic perspective. It focuses on key subjects of the new Prospectus Regulation, providing an in-depth analysis of each issue. The book then moves on to explain the domestic law on liability for a misleading prospectus, this issue being omitted from the Regulation. The law and practice in each of the key capital markets centres in Europe is analysed and compared, with the UK chapter covering the issues and possible solutions under Brexit. A chapter on securities litigation gives full consideration of conflicts of laws issues with reference to the Brussels I regulation, and the Rome I and II Regulations. The book concludes by looking to the future of disclosure practices in connection with securities offerings in the EU.

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Subunit-Selective Mutational Analysis and Tissue Culture Evaluations of the Interactions of the E138K and M184I Mutations in HIV-1 Reverse Transcriptase

Journal of Virology ◽

10.1128/jvi.00271-12 ◽

2012 ◽

Vol 86 (16) ◽

pp. 8422-8431 ◽

Cited By ~ 10

Author(s):

Hong-Tao Xu ◽

Maureen Oliveira ◽

Peter K. Quashie ◽

Matthew McCallum ◽

Yingshan Han ◽

...

Keyword(s):

Tissue Culture ◽

Reverse Transcriptase ◽

Evolutionary Dynamics ◽

Mutational Analysis ◽

Transcriptase Inhibitor ◽

Rnase H ◽

Viral Fitness ◽

Nonnucleoside Reverse Transcriptase Inhibitor ◽

The Impact ◽

Hiv 1

The emergence of HIV-1 drug resistance remains a major obstacle in antiviral therapy. M184I/V and E138K are signature mutations of clinical relevance in HIV-1 reverse transcriptase (RT) for the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and emtricitabine (FTC) and the second-generation (new) nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV), respectively, and the E138K mutation has also been shown to be selected by etravirine in cell culture. The E138K mutation was recently shown to compensate for the low enzyme processivity and viral fitness associated with the M184I/V mutations through enhanced deoxynucleoside triphosphate (dNTP) usage, while the M184I/V mutations compensated for defects in polymerization rates associated with the E138K mutations under conditions of high dNTP concentrations. The M184I mutation was also shown to enhance resistance to RPV and ETR when present together with the E138K mutation. These mutual compensatory effects might also enhance transmission rates of viruses containing these two mutations. Therefore, we performed tissue culture studies to investigate the evolutionary dynamics of these viruses. Through experiments in which E138K-containing viruses were selected with 3TC-FTC and in which M184I/V viruses were selected with ETR, we demonstrated that ETR was able to select for the E138K mutation in viruses containing the M184I/V mutations and that the M184I/V mutations consistently emerged when E138K viruses were selected with 3TC-FTC. We also performed biochemical subunit-selective mutational analyses to investigate the impact of the E138K mutation on RT function and interactions with the M184I mutation. We now show that the E138K mutation decreased rates of polymerization, impaired RNase H activity, and conferred ETR resistance through the p51 subunit of RT, while an enhancement of dNTP usage as a result of the simultaneous presence of both mutations E138K and M184I occurred via both subunits.

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Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

Current Pharmaceutical Design ◽

10.2174/1381612825666190304123545 ◽

2019 ◽

Vol 25 (7) ◽

pp. 750-773 ◽

Cited By ~ 11

Author(s):

Pabitra Narayan Samanta ◽

Supratik Kar ◽

Jerzy Leszczynski

Keyword(s):

Drug Targets ◽

Biological Activities ◽

Scoring Function ◽

Md Simulations ◽

Energy Calculation ◽

Binding Modes ◽

Macromolecular Systems ◽

In Silico Modeling ◽

Mathematical Algorithms ◽

The Impact

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

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Phytochemicals for drug discovery in Alzheimer’s disease: In silico Advances

Current Pharmaceutical Design ◽

10.2174/1381612826666200928161721 ◽

2020 ◽

Vol 26 ◽

Author(s):

Smriti Sharma ◽

Vinayak Bhatia

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drug Design ◽

In Silico ◽

Drug Targets ◽

Development Process ◽

Phytochemical Analysis ◽

Computational Drug Design ◽

Novel Drugs ◽

Game Changer

: The search for novel drugs that can prevent or control Alzheimer’s disease has attracted lot of attention from researchers across the globe. Phytochemicals are increasingly being used to provide scaffolds to design drugs for AD. In silico techniques, have proven to be a game-changer in this drug design and development process. In this review, the authors have focussed on current advances in the field of in silico medicine, applied to phytochemicals, to discover novel drugs to prevent or cure AD. After giving a brief context of the etiology and available drug targets for AD, authors have discussed the latest advances and techniques in computational drug design of AD from phytochemicals. Some of the prototypical studies in this area are discussed in detail. In silico phytochemical analysis is a tool of choice for researchers all across the globe and helps integrate chemical biology with drug design.

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The Catholic Diaspora—Experiences of Evacuation

10.1093/oso/9780198827023.003.0005 ◽

2018 ◽

Author(s):

Thomas Brodie

Keyword(s):

Urban Areas ◽

Religious Practice ◽

Catholic Clergy ◽

Profound Influence ◽

The Social ◽

Depth Analysis ◽

Nazi Era ◽

Mass Evacuation ◽

The Impact ◽

Pastoral Practice

This chapter analyses the impact exerted on the Catholic Church’s pastoral networks in Germany by the mass evacuation of laypeople from bombed urban areas as of 1941. Drawing on the voluminous correspondence of priests and curates despatched from the Rhineland and Westphalia to Saxony, Thuringia, Silesia, Austria, and elsewhere to minister to Catholic evacuees, this chapter provides in-depth analysis of the social and cultural histories of religious practice in wartime Germany. It demonstrates that the evacuation of laypeople—a topic long neglected within histories of wartime religious practice—exerted a profound influence on pastoral practice by the years 1943–5, placing unprecedented pressures on the Catholic clergy of the dioceses central to this study (Aachen, Cologne and Münster). This chapter therefore also casts new light on regionalism in Germany during the Nazi era.

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Understanding Motivating Operations and the Impact on the Function of Behavior

Intervention in School and Clinic ◽

10.1177/1053451220914901 ◽

2020 ◽

Vol 56 (2) ◽

pp. 119-122

Author(s):

Doris Adams Hill ◽

Theoni Mantzoros ◽

Jonté C. Taylor

Keyword(s):

Behavioral Interventions ◽

Special Educators ◽

Motivating Operations ◽

Behavior Intervention Plans ◽

Education Professionals ◽

Functional Behavior ◽

Special Education Professionals ◽

And Function ◽

And Behavior ◽

The Impact

Special educators are often considered the experts in their school when it comes to developing functional behavior assessments (FBA) and behavior intervention plans (BIP), yet rarely are they trained much beyond basic antecedents, behaviors, and consequences (ABC). This column discusses concepts that will expand special education professionals’ knowledge to make better decisions regarding interventions for the students they serve. Specifically, the focus is on motivating operations (MO) and function-based interventions and the implications of these on behavior. Knowledge of the concept of MOs can enhance a teacher’s ability to provide evidence-based interventions and more fully developed behavioral interventions for students in their purview.

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Decreased Medical Care During the COVID-19 Pandemic – A Comprehensive Analysis of Radiological Examinations

RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren ◽

10.1055/a-1368-5047 ◽

2021 ◽

Author(s):

Annette Aigner ◽

Bernd Hamm ◽

Florian Nima Fleckenstein ◽

Tazio Maleitzke ◽

Georg Böning ◽

...

Keyword(s):

Medical Care ◽

Control Period ◽

Surrogate Marker ◽

Medical Specialty ◽

Case Volume ◽

Medical Specialties ◽

Key Points ◽

Depth Analysis ◽

The Impact ◽

Radiological Examinations

Objectives As a cross-section discipline within the hospital infrastructure, radiological departments might be able to provide important information regarding the impact of the COVID-19 pandemic on healthcare. The goal of this study was to quantify changes in medical care during the first wave of the pandemic using radiological examinations as a comprehensive surrogate marker and to determine potential future workload. Methods A retrospective analysis of all radiological examinations during the first wave of the pandemic was performed. The number of examinations was compared to time-matched control periods. Furthermore, an in-depth analysis of radiological examinations attributed to various medical specialties was conducted and postponed examinations were extrapolated to calculate additional workload in the near future. Results A total of 596,760 examinations were analyzed. Overall case volumes decreased by an average of 41 % during the shutdown compared to the control period. The most affected radiological modalities were sonography (–54 %), X-ray (–47 %) followed by MRI (–42 %). The most affected medical specialty was trauma and orthopedics (–60 % case volume) followed by general surgery (–49 %). Examination numbers increased during the post-shutdown period leading to a predicted additional workload of up to 22 %. Conclusion This study shows a marked decrease in radiological examinations in total and among several core medical specialties, indicating a significant reduction in medical care during the first COVID-19 shutdown. Key Points: Citation Format

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Ontogenetic shift in the trophic role of the invasive killer shrimp Dikerogammarus villosus: a stable isotope study

Biological Invasions ◽

10.1007/s10530-021-02472-0 ◽

2021 ◽

Author(s):

Francesco Mancini ◽

Raffaele De Giorgi ◽

Alessandro Ludovisi ◽

Salvatrice Vizzini ◽

Giorgio Mancinelli

Keyword(s):

Dietary Habits ◽

Trophic Position ◽

Ecological Impact ◽

Central Italy ◽

Local Conditions ◽

Dikerogammarus Villosus ◽

Isotopic Signatures ◽

Depth Analysis ◽

Stable Isotope Study ◽

The Impact

AbstractThe introduction of the amphipod Dikerogammarus villosus in European fresh waters is to date recognized as a threat to the integrity of invaded communities. Predation by D. villosus on native benthic invertebrates is assumed as the key determinant of its ecological impact, yet available information describe the species as a primary consumer as well as a carnivore depending on local conditions. Here, we assessed the trophic position (TP) of D. villosus in Lake Trasimeno, a recently invaded lentic system in central Italy, using the CN isotopic signatures of individuals captured in winter spanning two orders of magnitude in body size. TP estimations were compared with those characterizing the native amphipod Echinogammarus veneris and other representative invertebrate predators. On average, D. villosus showed a trophic position higher than E. veneris, and comparable with that of odonate nymphs. An in-depth analysis revealed that large-sized individuals had a trophic position of 3.07, higher than odonates and close to that of the hirudinean predator Erpobdella octoculata, while small-sized specimens had a trophic position of 2.57, similar to that of E. veneris (2.41). These findings indicate that size-related ontogenetic shifts in dietary habits may per se vary the nature of the interaction between Dikerogammarus villosus and native invertebrates from competition to predation. Information collated from published isotopic studies corroborated the generality of our results. We conclude that intra-specific trophic flexibility may potentially amplify and make more multifaceted the impact of the species on other invertebrate species in invaded food webs.

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Impact of Carbohydrate Counting Error on Glycemic Control in Open-Loop Management of Type 1 Diabetes: Quantitative Assessment Through an in silico Trial

Journal of Diabetes Science and Technology ◽

10.1177/19322968211012392 ◽

2021 ◽

pp. 193229682110123

Author(s):

Chiara Roversi ◽

Martina Vettoretti ◽

Simone Del Favero ◽

Andrea Facchinetti ◽

Pratik Choudhary ◽

...

Keyword(s):

Type 1 Diabetes ◽

Glycemic Control ◽

In Silico ◽

Open Loop ◽

Random Errors ◽

Linear Regression Models ◽

Reference Case ◽

Counting Error ◽

The Impact

Background: In the management of type 1 diabetes (T1D), systematic and random errors in carb-counting can have an adverse effect on glycemic control. In this study, we performed an in silico trial aiming at quantifying the impact of different levels of carb-counting error on glycemic control. Methods: The T1D patient decision simulator was used to simulate 7-day glycemic profiles of 100 adults using open-loop therapy. The simulation was repeated for different values of systematic and random carb-counting errors, generated with Gaussian distribution varying the error mean from -10% to +10% and standard deviation (SD) from 0% to 50%. The effect of the error was evaluated by computing the difference of time inside (∆TIR), above (∆TAR) and below (∆TBR) the target glycemic range (70-180mg/dl) compared to the reference case, that is, absence of error. Finally, 3 linear regression models were developed to mathematically describe how error mean and SD variations result in ∆TIR, ∆TAR, and ∆TBR changes. Results: Random errors globally deteriorate the glycemic control; systematic underestimations lead to, on average, up to 5.2% more TAR than the reference case, while systematic overestimation results in up to 0.8% more TBR. The different time in range metrics were linearly related with error mean and SD ( R2>0.95), with slopes of [Formula: see text], [Formula: see text] for ∆TIR, [Formula: see text], [Formula: see text] for ∆TAR, and [Formula: see text], [Formula: see text] for ∆TBR. Conclusions: The quantification of carb-counting error impact performed in this work may be useful understanding causes of glycemic variability and the impact of possible therapy adjustments or behavior changes in different glucose metrics.

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