scholarly journals Investigating the mutational landscape of the SARS-CoV-2 Omicron variant via ab initio quantum mechanical modeling

2021 ◽  
Author(s):  
Luigi Genovese ◽  
Marco Zaccaria ◽  
Michael Farzan ◽  
Welkin Johnson ◽  
Babak Momeni
Keyword(s):  
Ab Initio ◽  
Hot Spots ◽  
Neutralizing Antibodies ◽  
Hot Spot ◽  
Point Mutations ◽  
Interaction Pattern ◽  
Weak Links ◽  
Quantum Mechanical ◽  
Binding Interaction

AbstractSARS-CoV-2 variant “Omicron” B1.1.529 was first identified in South Africa in November 2021. Given the large number of mutations in Omicron’s spike protein compared to the original Wuhan strain, its binding efficacy to the ACE2 receptor and its potential to escape antibodies are in the spotlight. Recently, we presented an ab initio quantum mechanical model to characterize the interactions of spike protein’s Receptor Binding Domain (RBD) with select antibodies and ACE2 variants. The model identified weak links among the residues constituting interactions with the human ACE2 receptor (hACE2), and also enabled us to characterize in silico mutated RBDs to identify potential Variants of Concern (VOC). In particular, we focused on the role of RBD residue 484 in the interaction of the Delta variant with ACE2 and neutralizing antibodies (nAbs). In this report, we apply our model to the Omicron VOC, and characterize its interaction pattern with hACE2. Our results show that (i) binding affinity with hACE2, compared to Delta, is considerably increased, possibly contributing to increased infectivity. (ii) The interaction pattern between B1.1.529 and hACE2 differs from previous variants by shifting the hot-spot interaction residues on hACE2, and potentially affecting nAbs efficacy. (iii) A K mutation in the RBD residue 484 can further improve Omicron’s binding of hACE2 and evasion of nAbs. Finally, we argue that a library of hot-spots for point-mutations can predict binding interaction energies of complex variants.

scholarly journals Role of N-Linked Glycans in the Functions of Hepatitis C Virus Envelope Proteins Incorporated into Infectious Virions

2010 ◽  
Vol 84 (22) ◽  
pp. 11905-11915 ◽  
Author(s):  
François Helle ◽  
Gabrielle Vieyres ◽  
Laure Elkrief ◽  
Costin-Ioan Popescu ◽  
Czeslaw Wychowski ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Point Mutations ◽  
Envelope Proteins ◽  
Envelope Glycoproteins ◽  
Virus Envelope ◽  
Humoral Immune ◽  
A Cell

ABSTRACT Hepatitis C virus (HCV) envelope glycoproteins are highly glycosylated, with generally 4 and 11 N-linked glycans on E1 and E2, respectively. Studies using mutated recombinant HCV envelope glycoproteins incorporated into retroviral pseudoparticles (HCVpp) suggest that some glycans play a role in protein folding, virus entry, and protection against neutralization. The development of a cell culture system producing infectious particles (HCVcc) in hepatoma cells provides an opportunity to characterize the role of these glycans in the context of authentic infectious virions. Here, we used HCVcc in which point mutations were engineered at N-linked glycosylation sites to determine the role of these glycans in the functions of HCV envelope proteins. The mutants were characterized for their effects on virus replication and envelope protein expression as well as on viral particle secretion, infectivity, and sensitivity to neutralizing antibodies. Our results indicate that several glycans play an important role in HCVcc assembly and/or infectivity. Furthermore, our data demonstrate that at least five glycans on E2 (denoted E2N1, E2N2, E2N4, E2N6, and E2N11) strongly reduce the sensitivity of HCVcc to antibody neutralization, with four of them surrounding the CD81 binding site. Altogether, these data indicate that the glycans associated with HCV envelope glycoproteins play roles at different steps of the viral life cycle. They also highlight differences in the effects of glycosylation mutations between the HCVpp and HCVcc systems. Furthermore, these carbohydrates form a “glycan shield” at the surface of the virion, which contributes to the evasion of HCV from the humoral immune response.

scholarly journals Anticipating future SARS-CoV-2 variants of concern through ab initio quantum mechanical modeling

2021 ◽  
Author(s):  
Marco Zaccaria ◽  
Luigi Genovese ◽  
Michael Farzan ◽  
William Dawson ◽  
Takahito Nakajima ◽  
...  
Keyword(s):  
Ab Initio ◽  
Density Functional ◽  
First Generation ◽  
Weak Link ◽  
Host Cells ◽  
Spike Protein ◽  
Quantum Mechanical ◽  
Protein Receptor ◽  
Protein Mutants

Evolved SARS-CoV-2 variants are currently challenging the efficacy of first-generation vaccines, largely through the emergence of spike protein mutants. Among these variants, Delta is presently the most concerning. We employ an ab initio quantum mechanical model based on Density Functional Theory to characterize the spike protein Receptor Binding Domain (RBD) interaction with host cells and gain mechanistic insight into SARS-CoV-2 evolution. The approach is illustrated via a detailed investigation of the role of the E484K RBD mutation, a signature mutation of the Beta and Gamma variants. The simulation is employed to: predict the depleting effect of the E484K mutation on binding the RBD with select antibodies; identify residue E484 as a weak link in the original interaction with the human receptor hACE2; and describe SARS-CoV-2 Wuhan strand binding to the bat Rhinolophus macrotis ACE2 as more optimized than the human counterpart. Finally, we predict the hACE2 binding efficacy of a hypothetical E484K mutation added to the Delta variant RBD, identifying a potential future variant of concern. Results can be generalized to other mutations, and provide useful information to complement existing experimental datasets of the interaction between randomly generated libraries of hACE2 and viral spike mutants. We argue that ab initio modeling is at the point of being aptly employed to inform and predict events pertinent to viral and general evolution.

scholarly journals A Role of Tyrosine Phosphatase in Acetylcholine Receptor Cluster Dispersal and Formation

1998 ◽  
Vol 141 (7) ◽  
pp. 1613-1624 ◽  
Author(s):  
Zhengshan Dai ◽  
H. Benjamin Peng
Keyword(s):  
Acetylcholine Receptor ◽  
Hot Spots ◽  
Hot Spot ◽  
Tyrosine Phosphatase ◽  
Cluster Formation ◽  
Muscle Cells ◽  
Achr Cluster ◽  
Discrete Manner ◽  
Achr Clustering

Innervation of the skeletal muscle involves local signaling, leading to acetylcholine receptor (AChR) clustering, and global signaling, manifested by the dispersal of preexisting AChR clusters (hot spots). Receptor tyrosine kinase (RTK) activation has been shown to mediate AChR clustering. In this study, the role of tyrosine phosphatase (PTPase) in the dispersal of hot spots was examined. Hot spot dispersal in cultured Xenopus muscle cells was initiated immediately upon the presentation of growth factor–coated beads that induce both AChR cluster formation and dispersal. Whereas the density of AChRs decreased with time, the fine structure of the hot spot remained relatively constant. Although AChR, rapsyn, and phosphotyrosine disappeared, a large part of the original hot spot–associated cytoskeleton remained. This suggests that the dispersal involves the removal of a key linkage between the receptor and its cytoskeletal infrastructure. The rate of hot spot dispersal is inversely related to its distance from the site of synaptic stimulation, implicating the diffusible nature of the signal. PTPase inhibitors, such as pervanadate or phenylarsine oxide, inhibited hot spot dispersal. In addition, they also affected the formation of new clusters in such a way that AChR microclusters extended beyond the boundary set by the clustering stimuli. Furthermore, by introducing a constitutively active PTPase into cultured muscle cells, hot spots were dispersed in a stimulus- independent fashion. This effect of exogenous PTPase was also blocked by pervanadate. These results implicate a role of PTPase in AChR cluster dispersal and formation. In addition to RTK activation, synaptic stimulation may also activate PTPase which acts globally to destabilize preexisting AChR hot spots and locally to facilitate AChR clustering in a spatially discrete manner by countering the action of RTKs.

Community-linked conservation using Devakad (sacred groves) in the Kodagu Model Forest, India

2012 ◽  
Vol 88 (03) ◽  
pp. 266-273 ◽  
Author(s):  
C.G. Kushalappa ◽  
S. Raghavendra
Keyword(s):  
Hot Spots ◽  
South India ◽  
Hot Spot ◽  
Current Status ◽  
Sacred Groves ◽  
Sacred Forest ◽  
Karnataka State ◽  
Conservation Effort ◽  
The Western Ghats

Kodagu District in Karnataka State, South India, part of the Western Ghats region, is described as one of the hottest hot spots of biodiversity in the world. This district can also be called a hot spot of sacred forest tradition due to the density and diversity of deities and communities that are part of an informal conservation concept based on Devakad, or sacred groves. This paper discusses the current status, threats and conservation initiatives undertaken by different stakeholders to revive this unique conservation concept and highlights the role of the Kodagu Model Forest as a key facilitator in the conservation effort.

scholarly journals Gold Nanorod Assemblies: The Roles of Hot-Spot Positioning and Anisotropy in Plasmon Coupling and SERS

Nanomaterials ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 942 ◽  
Author(s):  
Priyanka Dey ◽  
Verena Baumann ◽  
Jessica Rodríguez-Fernández
Keyword(s):  
Hot Spots ◽  
Hot Spot ◽  
Critical Role ◽  
Gold Nanorod ◽  
Plasmon Coupling ◽  
Surface Enhanced ◽  
Sybr Gold ◽  
Surface Enhanced Raman ◽  
Enhanced Raman Scattering

Plasmon-coupled colloidal nanoassemblies with carefully sculpted “hot-spots” and intense surface-enhanced Raman scattering (SERS) are in high demand as photostable and sensitive plasmonic nano-, bio-, and chemosensors. When maximizing SERS signals, it is particularly challenging to control the hot-spot density, precisely position the hot-spots to intensify the plasmon coupling, and introduce the SERS molecule in those intense hot-spots. Here, we investigated the importance of these factors in nanoassemblies made of a gold nanorod (AuNR) core and spherical nanoparticle (AuNP) satellites with ssDNA oligomer linkers. Hot-spot positioning at the NR tips was made possible by selectively burying the ssDNA in the lateral facets via controlled Ag overgrowth while retaining their hybridization and assembly potential at the tips. This strategy, with slight alterations, allowed us to form nanoassemblies that only contained satellites at the NR tips, i.e., directional anisotropic nanoassemblies; or satellites randomly positioned around the NR, i.e., nondirectional nanoassemblies. Directional nanoassemblies featured strong plasmon coupling as compared to nondirectional ones, as a result of strategically placing the hot-spots at the most intense electric field position of the AuNR, i.e., retaining the inherent plasmon anisotropy. Furthermore, as the dsDNA was located in these anisotropic hot-spots, this allowed for the tag-free detection down to ~10 dsDNA and a dramatic SERS enhancement of ~1.6 × 108 for the SERS tag SYBR gold, which specifically intercalates into the dsDNA. This dramatic SERS performance was made possible by manipulating the anisotropy of the nanoassemblies, which allowed us to emphasize the critical role of hot-spot positioning and SERS molecule positioning in nanoassemblies.

Hot Spot Heating from Impurities and Vacancies in a Crystalline Solid Under Rapid Compression

1992 ◽  
Vol 296 ◽  
Author(s):  
D. H. Tsai
Keyword(s):  
Molecular Dynamics ◽  
Hot Spots ◽  
Hot Spot ◽  
Host Lattice ◽  
Crystalline Solid ◽  
Vacancy Defects ◽  
Vacancy Clusters ◽  
Impurity Atoms ◽  
Bcc Lattice

AbstractThe role of impurity atoms and vacancy defects in the heating of hot spots in a 2D, fcc, monatomic lattice, subjected to rapid, 1D compression, has been studied by means of molecular dynamics. The interaction potential of the impurity atoms, their mass, and size were allowed to differ from those of the atoms in the host lattice. Several configurations of impurity and vacancy clusters were examined. The mechanisms of heating observed here were similar to those found earlier in a bcc lattice with vacancy defects but without impurities.

scholarly journals How Do Ocean Warm Anomalies Favor the Aggregation of Deep Convective Clouds?

2020 ◽  
Vol 77 (11) ◽  
pp. 3733-3745
Author(s):  
Sara Shamekh ◽  
Caroline Muller ◽  
Jean-Philippe Duvel ◽  
Fabio D’Andrea
Keyword(s):  
Hot Spots ◽  
Large Scale ◽  
Hot Spot ◽  
Spot Size ◽  
Large Scale Circulation ◽  
Convective Clouds ◽  
Sst Anomaly ◽  
Radiative Feedbacks ◽  
Self Aggregation

AbstractWe investigate the role of a warm sea surface temperature (SST) anomaly (hot spot of typically 3 to 5 K) on the aggregation of convection using cloud-resolving simulations in a nonrotating framework. It is well known that SST gradients can spatially organize convection. Even with uniform SST, the spontaneous self-aggregation of convection is possible above a critical SST (here 295 K), arising mainly from radiative feedbacks. We investigate how a circular hot spot helps organize convection, and how self-aggregation feedbacks modulate this organization. The hot spot significantly accelerates aggregation, particularly for warmer/larger hot spots, and extends the range of SSTs for which aggregation occurs; however, at cold SST (290 K) the aggregated cluster disaggregates if we remove the hot spot. A large convective instability over the hot spot leads to stronger convection and generates a large-scale circulation which forces the subsidence drying outside the hot spot. Indeed, convection over the hot spot brings the atmosphere toward a warmer temperature. The warmer temperatures are imprinted over the whole domain by gravity waves and subsidence warming. The initial transient warming and concomitant subsidence drying suppress convection outside the hot spot, thus driving the aggregation. The hot-spot-induced large-scale circulation can enforce the aggregation even without radiative feedbacks for hot spots sufficiently large/warm. The strength of the large-scale circulation, which defines the speed of aggregation, is a function of the hot spot fractional area. At equilibrium, once the aggregation is well established, the moist convective region with upward midtropospheric motion, centered over the hot spot, has an area surprisingly independent of the hot spot size.

Spatial Hotspot Analysis of Bucharest’s Urban Heat Island (UHI) Using Modis Data

2018 ◽  
Vol 18 (1) ◽  
pp. 14-22 ◽  
Author(s):  
Georgiana Grigoraș ◽  
Bogdan Urițescu
Keyword(s):  
Surface Temperature ◽  
Air Temperature ◽  
Land Surface Temperature ◽  
Hot Spots ◽  
Land Surface ◽  
Hot Spot ◽  
Monitoring Network ◽  
Residential Areas ◽  
Hotspot Analysis ◽  
The City

Abstract The aim of the study is to find the relationship between the land surface temperature and air temperature and to determine the hot spots in the urban area of Bucharest, the capital of Romania. The analysis was based on images from both moderate-resolution imaging spectroradiometer (MODIS), located on both Terra and Aqua platforms, as well as on data recorded by the four automatic weather stations existing in the endowment of The National Air Quality Monitoring Network, from the summer of 2017. Correlation coefficients between land surface temperature and air temperature were higher at night (0.8-0.87) and slightly lower during the day (0.71-0.77). After the validation of satellite data with in-situ temperature measurements, the hot spots in the metropolitan area of Bucharest were identified using Getis-Ord spatial statistics analysis. It has been achieved that the “very hot” areas are grouped in the center of the city and along the main traffic streets and dense residential areas. During the day the "very hot spots” represent 33.2% of the city's surface, and during the night 31.6%. The area where the mentioned spots persist, falls into the "very hot spot" category both day and night, it represents 27.1% of the city’s surface and it is mainly represented by the city center.

Sign in / Sign up

Export Citation Format

Share Document