Exploring and Learning the Universe of Protein Allostery Using Artificial Intelligence Augmented Biophysical and Computational Approaches

Journal of Chemical Information and Modeling, Год журнала: 2023, Номер 63(5), С. 1413 - 1428

Опубликована: Фев. 24, 2023

Allosteric mechanisms are commonly employed regulatory tools used by proteins to orchestrate complex biochemical processes and control communications in cells. The quantitative understanding characterization of allosteric molecular events among major challenges modern biology require integration innovative computational experimental approaches obtain atomistic-level knowledge the states, interactions, dynamic conformational landscapes. growing body studies empowered emerging artificial intelligence (AI) technologies has opened up new paradigms for exploring learning universe protein allostery from first principles. In this review we analyze recent developments high-throughput deep mutational scanning functions; applications latest adaptations Alpha-fold structural prediction methods dynamics allostery; frontiers integrating machine enhanced sampling techniques advances systems. We also highlight SARS-CoV-2 spike (S) revealing an important often hidden role regulation driving functional changes, binding interactions with host receptor, escape S which critical viral infection. conclude a summary outlook future directions suggesting that AI-augmented biophysical computer simulation beginning transform toward systematic landscapes, may bring about revolution drug discovery.

Язык: Английский

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Evolutionary rate of SARS-CoV-2 increases during zoonotic infection of farmed mink

Virus Evolution, Год журнала: 2023, Номер 9(1)

Опубликована: Янв. 1, 2023

Abstract To investigate genetic signatures of adaptation to the mink host, we characterised evolutionary rate heterogeneity in mink-associated severe acute respiratory syndrome coronaviruses (SARS-CoV-2). In 2020, first detected anthropozoonotic spillover event SARS-CoV-2 occurred farms throughout Europe and North America. Both spill-back lineages into human population spread surrounding wildlife were reported, highlighting potential formation a zoonotic reservoir. Our findings suggest that underwent an episodic increase upon introduction host before returning normal range observed humans. Furthermore, could have circulated for month detection, during this period, estimates between 3 × 10–3 1.05 10–2 (95 per cent HPD, with mean 6.59 10–3) four- thirteen-fold compared As there is evidence unique mutational patterns within lineages, explored emergence four mink-specific Spike protein amino acid substitutions Y453F, S1147L, F486L, Q314K. We found mutation Y453F emerged early multiple outbreaks mutations F486L Q314K may co-occur. undergoes brief, but considerable, response greater selective pressures species jumps, which lead occurrence mutations. These emphasise necessity ongoing surveillance infections future.

Язык: Английский

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Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 18, 2024

Язык: Английский

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Mutational dynamics of SARS-CoV-2: Impact on future COVID-19 vaccine strategies

Heliyon, Год журнала: 2024, Номер 10(9), С. e30208 - e30208

Опубликована: Апрель 25, 2024

The rapid emergence of multiple strains Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has sparked profound concerns regarding the ongoing evolution virus and its potential impact on global health. Classified by World Health Organization (WHO) as variants concern (VOC), these exhibit heightened transmissibility pathogenicity, posing significant challenges to existing vaccine strategies. Despite widespread vaccination efforts, continual SARS-CoV-2 presents a formidable obstacle achieving herd immunity. Of particular is coronavirus spike (S) protein, pivotal viral surface protein crucial for host cell entry infectivity. Mutations within S have been shown enhance confer resistance antibody-mediated neutralization, undermining efficacy traditional platforms. Moreover, undergoes molecular under selective immune pressure, leading diverse with distinct mutation profiles. This review underscores urgent need vigilance adaptation in development efforts combat evolving landscape mutations ensure long-term effectiveness immunization campaigns.

Язык: Английский

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Placental transfer dynamics and durability of maternal COVID-19 vaccine-induced antibodies in infants

iScience, Год журнала: 2024, Номер 27(3), С. 109273 - 109273

Опубликована: Фев. 20, 2024

Completion of a COVID-19 vaccination series during pregnancy effectively reduces hospitalization among infants less than 6 months age. The dynamics transplacental transfer maternal vaccine-induced antibodies, and their persistence in at 2, 6, 9, 12 months, have implications for new vaccine development optimal timing administration pregnancy. We evaluated anti-COVID antibody IgG subclass, Fc-receptor binding profile, activity against wild-type Spike RBD plus five variants concern (VOCs) 153 serum samples from 100 infants. Maternal IgG1 IgG3 responses persisted 2- 6-month to greater extent the other subclasses, with high antibodies placental neonatal FcγR3A. Lowest was observed Omicron RBD-specific region. timing, capabilities, fetal sex, VOC all impact through

Язык: Английский

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Intrinsic D614G and P681R/H mutations in SARS-CoV-2 VoCs Alpha, Delta, Omicron and viruses with D614G plus key signature mutations in spike protein alters fusogenicity and infectivity

Medical Microbiology and Immunology, Год журнала: 2022, Номер 212(1), С. 103 - 122

Опубликована: Дек. 30, 2022

Abstract The SARS-CoV-2 virus has been rapidly evolving over the time and genetic variation led to generation of Variants Concerns (VoC), which have shown increased fitness. These VoC viruses contain key mutations in spike protein allowed better survival evasion host defense mechanisms. D614G mutation domain is found majority VoC; additionally, P681R/H at S1/S2 furin cleavage site junction also be highly conserved major VoCs; Alpha, Delta, Omicron, its’ current variants. impact these alterations VoCs on cell entry, transmissibility, infectivity not clearly identified. In our study, Delta + P681R synthetic double mutant pseudoviruses showed a significant increase cell-to-cell fusion infectivity. contrast, Omicron P681H single TMPRSS2 independent less as compared mutants. Addition exogenous trypsin further enhanced Omicron. Furthermore, susceptibility both E64d Camostat mesylate inhibitors suggesting, that could exploit endosomal dependent entry pathways virus. Taken together, results indicate are pivotal might favoring replication different compartments, thus allowing balance vs selection for long-term adaptation.

Язык: Английский

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Neutralization of the SARS-CoV-2 Deltacron and BA.3 Variants

New England Journal of Medicine, Год журнала: 2022, Номер 386(24), С. 2340 - 2342

Опубликована: Май 18, 2022

Язык: Английский

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COVID-19 vaccination and BA.1 breakthrough infection induce neutralising antibodies which are less efficient against BA.4 and BA.5 Omicron variants, Israel, March to June 2022

Eurosurveillance, Год журнала: 2022, Номер 27(30)

Опубликована: Июль 28, 2022

This work evaluated neutralising antibody titres against wild type (WT) SARS-CoV-2 and four Omicron variants (BA.1, BA.2, BA.4 BA.5) in healthcare workers who had breakthrough BA.1 infection. infection individuals vaccinated three or times before resulted increased antibodies the WT virus. The fourth vaccine dose did not further improve efficiency over third all variants, especially BA.5. An Omicron-specific may be indicated.

Язык: Английский

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Hybrid Immunity Shifts the Fc-Effector Quality of SARS-CoV-2 mRNA Vaccine-Induced Immunity

mBio, Год журнала: 2022, Номер 13(5)

Опубликована: Авг. 24, 2022

Despite the robust immunogenicity of SARS-CoV-2 mRNA vaccines, emerging data have revealed enhanced neutralizing antibody and T cell cross-reactivity among individuals that previously experienced COVID-19, pointing to a hybrid immune advantage with infection-associated priming. Beyond antibodies immunity, mounting point potential role for additional effector functions, including opsinophagocytic activity, in resolution symptomatic COVID-19. Whether immunity modifies Fc-effector profile vaccine-induced response remains incompletely understood. Thus, here we profiled specific humoral group without prior As expected, Spike-specific titers were following primary dose vaccine but similar those achieved by naive vaccinees after second dose. Conversely, Fc-receptor binding levels higher immunization COVID-19 remained compared individuals, suggestive selective improvement quality, rather than quantity, response. while magnitude alone may suggest any two antigen exposures-either or doses alone-represent comparable prime/boost immunologic education, find offers qualitatively improved able better leverage functions against conserved regions virus. IMPORTANCE Recent indicates who experience combination infection, "hybrid immunity," receive vaccination infection alone. While previous accelerates first vaccination, subsequent demonstrate negligible increases immunity. Here, using systems serology, observed unique induced marked induction Fc-recruiting directed at region viral Spike antigen, S2-domain, lower only received vaccination. clearly redirects immunodominance, resulting functional most highly which be key protection existing variants concern. next-generation vaccines mimic drive balanced confer disease.

Язык: Английский

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The emergence of SARS-CoV-2 Omicron subvariants: current situation and future trends

Infezioni in Medicina, Год журнала: 2022, Номер 30(4)

Опубликована: Дек. 1, 2022

The SARS-CoV-2 Omicron variant (B.1.1.529) has been the most recent of concern (VOC) established by World Health Organization (WHO). Because its greater infectivity and immune evasion, this quickly became dominant type circulating worldwide. Our literature review thoroughly explains current state emergence, particularly comparing different omicron subvariants, including BA.2, BA.1, BA.3. Such elaboration would be based on structural variations, mutations, clinical manifestation, transmissibility, pathogenicity, vaccination effectiveness. notable difference between three subvariants is insufficiency deletion (Δ69-70) in spike protein, which results a lower detection rate (S) gene target known as failure (SGTF). Furthermore, BA.2 had stronger affinity to human Angiotensin-converting Enzyme (hACE2) receptor than other sub-lineages. Regarding number BA.1.1 (40), followed BA.3, BA.3 with 39, 34, 31 respectively. In addition, have transmissibility sub-lineages (BA.1 BA.1.1). These characteristics are primarily responsible for Omicron's vast geographical spread high contagiousness rates,

Язык: Английский

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