Structural bioinformatics analysis of SARS-CoV-2 variants reveals higher hACE2 receptor binding affinity for Omicron B.1.1.529 spike RBD compared to wild type reference

Durmaz, Vedat; Köchl, Katharina; Krassnigg, A.; Parigger, Lena; Hetmann, Michael; Singh, Amit; Nutz, Daniel; Korsunsky, Alexander M.; Kahler, Ursula; König, Centina; Chang, Lee Sin; Krebs, Marius; Bassetto, Riccardo; Pavkov‐Keller, Tea; Resch, Verena; Gruber, Karl; Steinkellner, Georg; Gruber, Christian

doi:10.1038/s41598-022-18507-y

Cited by 16 publications

(18 citation statements)

References 90 publications

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“…Also, our data clearly point out that the delta variant has a weaker affinity towards hACE-2 compared to wild type SARS-CoV-2; which is also in agreement with published reports. [ 23 , 41 ]…”

Section: Resultsmentioning

confidence: 99%

Structural Profiles of SARS-CoV-2 Variants in India

et al. 2022

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India was severely affected by several waves of SARS-CoV-2 infection that occurred during April–June 2021 (second wave) and December 2021–January 2022 (third wave) and thereafter, resulting in >10 million new infections and a significant number of deaths. Global Initiative on Sharing Avian Influenza Data database was used to collect the sequence information of ~10,000 SARS-CoV-2 patients from India and our sequence analysis identified three variants B.1.1.7 (alpha, α), B1.617.2 (delta, Δ), B.1.1.529 (Omicron, Oo) and one Omicron sub-variant BA.2.75 as the primary drivers for SARS-CoV-2 waves in India. Structural visualization and analysis of important mutations of alpha, delta, Omicron and its sub-variants of SARS-CoV-2 Receptor-Binding Domain (RBD) was performed and our analysis clearly shows that mutations occur throughout the RBD, including the RBD surface responsible for human angiotensin-converting enzyme 2 (hACE-2) receptor-binding. A comparison between alpha, delta and omicron variants/sub-variants reveals many omicron mutations in the hACE-2 binding site and several other mutations within 5 Å of this binding region. Further, computational analysis highlights the importance of electrostatic interactions in stabilizing RBD-hACE-2-binding, especially in the omicron variant. Our analysis explores the likely role of key alpha, delta and omicron mutations on binding with hACE-2. Taken together, our study provides novel structural insights into the implications of RBD mutations in alpha, delta and omicron and its sub-variants that were responsible for India’s SARS-CoV-2 surge. Supplementary Information The online version contains supplementary material available at 10.1007/s00284-022-03094-y.

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Section: Resultsmentioning

confidence: 99%

Structural Profiles of SARS-CoV-2 Variants in India

et al. 2022

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“…Based on these observations and data, we devised a workflow using a combination of standard techniques and our point-cloud technology: First, we used extensive molecular dynamics (MD) simulations to identify hACE2 mutations that strengthen the interaction with the spike RBD. To this end, we employed an empirical scoring function (ESF) closely related to the linear interaction energy (LIE) method, which has been calibrated on experimental binding data, as described previously 30 . We performed virus-neutralization assays to evaluate the potential of four hACE2 variants linked to an Fc segment of human IgG1 (hACE2-Fc) to inhibit the spread of wild-type SARS-CoV-2 as well as SARS-CoV-2 Beta, which has acquired mutations that reduced the binding to class 1 antibodies 5 .…”

Section: Introductionmentioning

confidence: 99%

“…The MD-simulation data were combined with hACE2- and spike RBD Cataphore Halos 30 to train an artificial neural network (ANN). Our deep-learning models presented here are intended as a tool to predict binding affinities of the SARS-CoV-2 spike protein with hACE2 variants.…”

Section: Introductionmentioning

confidence: 99%

Optimizing variant-specific therapeutic SARS-CoV-2 decoys using deep-learning-guided molecular dynamics simulations

Köchl

Schopper²,

Durmaz³

et al. 2023

Sci Rep

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Treatment of COVID-19 with a soluble version of ACE2 that binds to SARS-CoV-2 virions before they enter host cells is a promising approach, however it needs to be optimized and adapted to emerging viral variants. The computational workflow presented here consists of molecular dynamics simulations for spike RBD-hACE2 binding affinity assessments of multiple spike RBD/hACE2 variants and a novel convolutional neural network architecture working on pairs of voxelized force-fields for efficient search-space reduction. We identified hACE2-Fc K31W and multi-mutation variants as high-affinity candidates, which we validated in vitro with virus neutralization assays. We evaluated binding affinities of these ACE2 variants with the RBDs of Omicron BA.3, Omicron BA.4/BA.5, and Omicron BA.2.75 in silico. In addition, candidates produced in Nicotiana benthamiana, an expression organism for potential large-scale production, showed a 4.6-fold reduction in half-maximal inhibitory concentration (IC50) compared with the same variant produced in CHO cells and an almost six-fold IC50 reduction compared with wild-type hACE2-Fc.

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“…Because of the importance of the spike protein’s genetic drift ( 14 ), efforts are being made to closely monitor and track changes relevant to infectiousness ( 15 , 16 ) and immunity ( 17 , 18 ). However, since drug-discovery efforts targeting M pro ( 19 ) had already begun as early as January 2020, computational models and experimentally determined protein structures needed to identify covalent ( 20 , 21 ) and non-covalent inhibitors ( 22 , 23 ) were and are mainly based on the “wild-type” version of M pro as it was present in the first sequenced SARS-CoV-2 strain ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Recent changes in the mutational dynamics of the SARS-CoV-2 main protease substantiate the danger of emerging resistance to antiviral drugs

Parigger

Krassnigg²,

Schopper³

et al. 2022

Front. Med.

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IntroductionThe current coronavirus pandemic is being combated worldwide by nontherapeutic measures and massive vaccination programs. Nevertheless, therapeutic options such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main-protease (Mpro) inhibitors are essential due to the ongoing evolution toward escape from natural or induced immunity. While antiviral strategies are vulnerable to the effects of viral mutation, the relatively conserved Mpro makes an attractive drug target: Nirmatrelvir, an antiviral targeting its active site, has been authorized for conditional or emergency use in several countries since December 2021, and a number of other inhibitors are under clinical evaluation. We analyzed recent SARS-CoV-2 genomic data, since early detection of potential resistances supports a timely counteraction in drug development and deployment, and discovered accelerated mutational dynamics of Mpro since early December 2021.MethodsWe performed a comparative analysis of 10.5 million SARS-CoV-2 genome sequences available by June 2022 at GISAID to the NCBI reference genome sequence NC_045512.2. Amino-acid exchanges within high-quality regions in 69,878 unique Mpro sequences were identified and time- and in-depth sequence analyses including a structural representation of mutational dynamics were performed using in-house software.ResultsThe analysis showed a significant recent event of mutational dynamics in Mpro. We report a remarkable increase in mutational variability in an eight-residue long consecutive region (R188-G195) near the active site since December 2021.DiscussionThe increased mutational variability in close proximity to an antiviral-drug binding site as described herein may suggest the onset of the development of antiviral resistance. This emerging diversity urgently needs to be further monitored and considered in ongoing drug development and lead optimization.

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Structural bioinformatics analysis of SARS-CoV-2 variants reveals higher hACE2 receptor binding affinity for Omicron B.1.1.529 spike RBD compared to wild type reference

Cited by 16 publications

References 90 publications

Structural Profiles of SARS-CoV-2 Variants in India

Structural Profiles of SARS-CoV-2 Variants in India

Optimizing variant-specific therapeutic SARS-CoV-2 decoys using deep-learning-guided molecular dynamics simulations

Recent changes in the mutational dynamics of the SARS-CoV-2 main protease substantiate the danger of emerging resistance to antiviral drugs

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