#COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy of Delta SARS-CoV-2 in a Respiratory Aerosol

Dommer, Abigail C.; Casalino, Lorenzo; Kearns, Fiona L.; Rosenfeld, Mia A.; Wauer, Nicholas; Ahn, Surl-Hee; Russo, John D.; Oliveira, A. Sofia F.; Morris, Clare K.; Bogetti, Anthony T.; Trifan, Anda; Brace, Alexander; Sztain, Terra; Clyde, Austin; Ma, Huadóng; Chennubhotla, Chakra; Lee, Hyungro; Turilli, Matteo; Khalid, Syma; Tamayo-Mendoza, Teresa; Welborn, Matthew; Christiansen, A.V.; Smith, Daniel G. A.; Qiao, Zhuoran; Sirumalla, Sai Krishna; Manby, Frederick R.; Anandkumar, Anima; Hardy, David J.; Phillips, J. C.; Stern, Abraham C.; Romero, Josh; Clark, David; Dorrell, Mitchell; Maiden, Tom; Huang, Lei; McCalpin, John D.; Woods, Christopher; Gray, Alan; Williams, Matt; Barker, Bryan; Rajapaksha, Harinda; Pitts, Richard; Gibbs, Tom; Stone, John E.; Zuckerman, Daniel M.; Muholland, Adrian; Miller, Thomas F.; Jha, Shantenu; Ramanathan, Arvind; Chong, Lillian T.; Amaro, Rommie E.

doi:10.1101/2021.11.12.468428

Cited by 21 publications

(20 citation statements)

References 82 publications

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“…D-NEMD simulations provide an effective approach to characterise allosteric effects (e.g. ( 29, 30 )), effects of pH changes ( 26 ) and other functionally important properties and will be helpful to investigate further emerging variants. We note that the simulations here compare spike proteins without glycans; as discussed above and elsewhere ( 29 ), the presence of glycans (covering the outside of the protein) is unlikely to qualitatively alter the internal mechanical response of the protein.…”

Section: Discussionmentioning

confidence: 99%

“…For the original (‘Wuhan’) spike, this approach identified allosteric connections between the fatty acid site and functionally important regions of the protein (including the RBM, furin cleavage site and FP-surrounding regions) and mapped the networks that connect them to the FA site ( 29, 30 ). D-NEMD simulations have also been used to investigate the effects of pH on the Delta spike ( 26 ).…”

Section: Introductionmentioning

confidence: 99%

“…Biomolecular simulations have provided molecular level insight into SARS-CoV-2 spike structure and dynamics, uncovering the effect of mutations, predicting interactions and revealing allosteric connections in the protein (e.g. (3,13,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)), including providing insight into the complex role of the FA site (13,17,29,30). Equilibrium molecular dynamics (MD) simulations indicated persistent and stable interactions between LA and the spike trimer (13,17), and that binding of LA rigidifies the FA binding site (17).…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 spike variants differ in their allosteric response to linoleic acid

Oliveira

Shoemark

Davidson

et al. 2022

Preprint

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The SARS-CoV-2 spike protein contains a fatty acid binding site, also found in some other coronaviruses (e.g. SARS-CoV), which binds linoleic acid and is functionally important. When occupied by linoleic acid, it reduces infectivity, by ‘locking’ the spike in a less infectious conformation. Here, we use dynamical-nonequilibrium molecular dynamics (D-NEMD) simulations to compare the response of spike variants to linoleic acid removal. These simulations show that the fatty acid site is coupled to functional regions of the protein, some of them far from the site (e.g. in the receptor-binding motif, N-terminal domain, the furin cleavage site located in position 679-685 and the fusion peptide-surrounding regions) and identify the allosteric networks involved in these connections. Comparison of the response of the original (‘Wuhan’) spike with four variants: Alpha, Delta, Delta plus and Omicron BA.1 show that the variants differ significantly in their response to linoleic acid removal. The allosteric connections to the fatty acid site on Alpha are generally similar to the original protein, except for the receptor-binding motif and S71-R78 region which show a weaker link to the FA site. In contrast, Omicron is the most affected variant exhibiting significant differences in the receptor-binding motif, N-terminal domain, V622-L629 and the furin cleavage site. These differences in allosteric modulation may be of functional relevance, e.g. in differences in transmissibility and virulence. Experimental comparison of the effects of linoleic acid on different variants is warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

SARS-CoV-2 spike variants differ in their allosteric response to linoleic acid

Oliveira

Shoemark

Davidson

et al. 2022

Preprint

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“…Although recent technical developments of cryo-ET have enabled the reconstruction of intact SARS-CoV-2, the structure has been limited to nanometer resolution [2, 3]. In the meanwhile, computational studies have also provided highly valuable information on the structure of the virus [4–6], but the existing structural models have been limited to a coarse-grained (CG) scale, focusing only on the virus envelope, or constructed without considering the protein localization from the in situ cryo-ET data. Therefore, we set out to construct an atomistic model of SARS-CoV-2 by fully employing the latest cryo-ET data [2], in combination with the available experimentally resolved protein structures, structure prediction and modeling methods, as well as molecular dynamics (MD) simulations.…”

Section: Textmentioning

confidence: 99%

Toward Atomistic Models of Intact SARS-CoV-2 via Martini Coarse-Grained Molecular Dynamics Simulations

Wang

et al. 2022

Preprint

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The causative pathogen of Coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enveloped virus assembled by a lipid envelope, a positive-sense single-stranded RNA, and four structural proteins: the spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins. Extensive experimental and computational studies have been carried out to reveal the architecture of the virus, but an intact and high-resolution structure of the virus is still desired. In this work, we construct atomistic models of the intact SARS-CoV-2 (without complete RNA) by fully employing the latest cryo-ET data, in combination with the available experimentally resolved protein structures, structure prediction and modeling methods, as well as coarse-grained molecular dynamics (MD) simulations. The atomistic model will not only provide a 3D structure for scientific demonstration and education, but also offer a framework for future exascale all-atom MD simulations to understand the dynamics of the intact virus and its mutations.

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“…Here, we have used a combination of equilibrium and dynamical-nonequilibriumcmolecular dynamics (D-NEMD) simulations to investigate the basis of partial agonism in the (α4)2(β2)3 subtype of the human α4β2 nAChRs and map the (structural and dynamic) differences induced by full and partial agonists in this receptor. In our previous studies, we have demonstrated how the combination of both equilibrium and nonequilibrium simulations is a powerful approach to study signal propagation and allostery in proteins (44)(45)(46)(47)(48)(49), including nAChRs (50,51). Now, a large set of D-NEMD simulations were performed together with extensive equilibrium simulations of the (α4)2(β2)3 subtype with either acetylcholine (full agonist) or nicotine (partial agonist) bound.…”

Section: Introductionmentioning

confidence: 99%

Structural and temporal basis for agonism in the α4β2 nicotinic acetylcholine receptor

Oliveira

Bermúdez

Gallagher

et al. 2022

Preprint

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Despite decades of study, the structural mechanisms underpinning agonist efficacy in pentameric ligand-gated ion channels remain poorly understood. Here, a combination of extensive equilibrium and dynamical-nonequilibrium molecular dynamics simulations was used to obtain a detailed description of the structural and dynamic changes induced within the human α4β2 nicotinic acetylcholine receptor by a full and a partial agonist, namely acetylcholine and nicotine, and map how these rearrangements propagate within this receptor. These simulations reveal how the agonists modulate the patterns associated with intra and inter-domain communication and the evolution of the agonist-specific structural rearrangements. For the first time, we show that full and partial agonists, although generally using similar routes for through-receptor signal transmission, induce different amplitudes of conformational rearrangements in key functional motifs, thus impacting the rates of signal propagation within the protein. The largest agonist-induced conformational differences are located in the Cys loop, loops C and α1-β1 in the α4 subunit, loops F and β1-β2 in the β2 subunit and in the extracellular selectivity filter.

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#COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy of Delta SARS-CoV-2 in a Respiratory Aerosol

Cited by 21 publications

References 82 publications

SARS-CoV-2 spike variants differ in their allosteric response to linoleic acid

SARS-CoV-2 spike variants differ in their allosteric response to linoleic acid

Toward Atomistic Models of Intact SARS-CoV-2 via Martini Coarse-Grained Molecular Dynamics Simulations

Structural and temporal basis for agonism in the α4β2 nicotinic acetylcholine receptor

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