SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

Cell Reports, Год журнала: 2022, Номер 40(7), С. 111220 - 111220

Опубликована: Авг. 1, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants concern (VOCs). Here, we examine the contribution NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta Kappa variants) NTDs generating pseudotyped lentivirus. We find that Delta on a or wild-type (WT) background increases S1/S2 cleavage efficiency virus entry, specifically lung cells airway organoids, through use TMPRSS2. exhibits increased fusogenicity could be conferred WT transfer. However, chimeras Omicron BA.1 BA.2 with do not show more efficient TMPRSS2 fusogenicity. conclude allosterically modulates spike-mediated functions context-dependent manner, allosteric interactions may lost when combining regions from distantly related VOCs.

Язык: Английский

---

Evolution of the SARS-CoV-2 Omicron spike

Cell Reports, Год журнала: 2023, Номер 42(12), С. 113444 - 113444

Опубликована: Ноя. 18, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern, first identified in November 2021, rapidly spread worldwide and diversified into several subvariants. spike (S) protein accumulated an unprecedented number sequence changes relative to previous variants. In this review, we discuss how S structural features modulate host cell receptor binding, virus entry, immune evasion highlight these differentiate from We also examine key properties track across the still-evolving subvariants importance continuing surveillance evolution over time.

Язык: Английский

---

Markov State Models and Perturbation-Based Approaches Reveal Distinct Dynamic Signatures and Hidden Allosteric Pockets in the Emerging SARS-Cov-2 Spike Omicron Variant Complexes with the Host Receptor: The Interplay of Dynamics and Convergent Evolution Modulates Allostery and Functional Mechanisms

Journal of Chemical Information and Modeling, Год журнала: 2023, Номер 63(16), С. 5272 - 5296

Опубликована: Авг. 7, 2023

The new generation of SARS-CoV-2 Omicron variants displayed a significant growth advantage and increased viral fitness by acquiring convergent mutations, suggesting that the immune pressure can promote evolution leading to sudden acceleration evolution. In current study, we combined structural modeling, microsecond molecular dynamics simulations, Markov state models characterize conformational landscapes identify specific dynamic signatures spike complexes with host receptor ACE2 for recently emerged highly transmissible XBB.1, XBB.1.5, BQ.1, BQ.1.1 variants. Microsecond simulations Markovian modeling provided detailed characterization functional states revealed thermodynamic stabilization XBB.1.5 subvariant, which be contrasted more BQ.1 subvariants. Despite considerable similarities, mutations induce unique distributions states. results suggested variant-specific changes mobility in interfacial loops receptor-binding domain protein fine-tuned through crosstalk between could provide an evolutionary path modulation escape. By combining atomistic analysis perturbation-based approaches, determined important complementary roles mutation sites as effectors receivers allosteric signaling involved plasticity regulation communications. This study also hidden pockets control distribution flexible adaptable regions.

Язык: Английский

---

Association Between Vaccination Coverage Disparity and the Dynamics of the COVID-19 Delta and Omicron Waves in the US

Frontiers in Medicine, Год журнала: 2022, Номер 9

Опубликована: Июнь 14, 2022

Objective The US recently suffered the fourth and most severe wave of COVID-19 pandemic. This was driven by SARS-CoV-2 Omicron, a highly transmissible variant that infected even vaccinated people. Vaccination coverage disparities have played an important role in shaping epidemic dynamics. Analyzing epidemiological impact this uneven vaccination is essential to understand local differences spread outcomes Omicron wave. Therefore, objective study quantify disparity dynamics pandemic during third waves Delta variants. Methods cross-sectional used cases, deaths, from 2,417 counties. main were new cases (incidence rate per 100,000 people) related deaths (mortality at county level exposure variable level. Geospatial data visualization analyses estimate association between incidence mortality rates for waves. Results During wave, areas with high (>60%) experienced 1.4 (95% confidence interval [CI] 1.3–1.7) times higher compared low (<40%). However, 1.6 CI 1.5–1.7) these low-vaccinated than 60%. As result, had 2.2 2.1–2.2) case-fatality ratio. clustering analysis showed more defined spatial structure clusters located southern states. Conclusions Despite emergence virus variants differential transmission potential, protective effect vaccines keeps generating marked distribution critical health outcomes, having largest US. Vulnerable communities residing areas, which are mostly rural, suffering highest burden era.

Язык: Английский

---

SARS-CoV-2 Omicron Variant Binds to Human Cells More Strongly than the Wild Type: Evidence from Molecular Dynamics Simulation

The Journal of Physical Chemistry B, Год журнала: 2022, Номер 126(25), С. 4669 - 4678

Опубликована: Июнь 20, 2022

The emergence of the variant concern Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 has aggravated Covid-19 pandemic due to its very contagious ability. high infection rate may be binding affinity human cells, but both experimental and computational studies have yielded conflicting results on this issue. Some shown that binds angiotensin-converting enzyme (hACE2) more strongly than wild type (WT), other reported comparable affinities. To shed light open problem, in work, we calculated free energy receptor domain (RBD) WT spike protein hACE2 using all-atom molecular dynamics simulation mechanics Poisson-Boltzmann surface area method. We showed cells increased RBD charge, which enhances electrostatic interaction with negatively charged hACE2. N440K, T478K, E484A, Q493R, Q498R mutations been found play a critical role stability RBD-hACE2 complex. effect homogeneous heterogeneous models glycans coating viral peptidyl was examined. Although total is not sensitive glycan model, distribution per-residue energies depends it. In addition, little

Язык: Английский

---