Biology subjects

Amaro, R. E.

Publications and source records attributed to Amaro, R. E..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Breaking Down the Bottlebrush: Atomically-Detailed Structural Dynamics of Mucins

Mucins, the biomolecular components of mucus, are glycoproteins that form a thick physical barrier at all tissue-air interfaces, forming a first line of defense against pathogens. Structural features of mucins and their interactions with other biomolecules remain largely unexplored due to challenges associated with their high-resolution characterization. Combining limited mass spectrometry glycomics and protein sequencing data, we present all-atom, explicitly solvated molecular dynamics simulations of a major respiratory mucin, MUC5B. We detail key forces and degrees of freedom imposed by the extensive O-glycosylation, which imbue the canonically observed bottlebrush-like structures to these otherwise intrinsically disordered protein backbones. We compare our simulation results to static structures observed in recent scanning tunneling microscopy experiments, as well as other published experimental efforts. Our work presents a generalizable framework for investigating the dynamics and interactions of mucins, which can inform on structural details currently inaccessible to experimental techniques.

biophysics↗

bioRxiv2023

Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike

The trimeric spike protein plays an essential role in the SARS-CoV-2 virus lifecycle, facilitating virus entry through binding to the cellular receptor angiotensin-converting enzyme 2 (ACE2) and mediating viral-host membrane fusion. The SARS-CoV-2 spike contains a fatty acid (FA) binding site at the interface between two neighbouring receptor-binding domains. This site, also found in some other coronaviruses, binds free fatty acids such as linoleic acid. Binding at this site locks the spike in a non-infectious, closed conformation. This site is coupled to functionally important regions, but the effects of glycans on these allosteric effects have not been investigated. Understanding allostery and how this site modulates the behaviour of the spike protein could potentiate the development of promising alternative strategies for new coronavirus therapies. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to investigate allosteric effects of the FA site in the fully glycosylated spike of the original SARS-CoV-2 ancestral variant. The results show allosteric networks that connect the FA site to important functional regions of the protein, including some more than 40 [A] away, including the receptor binding motif, an antigenic supersite in the N-terminal domain, the furin cleavage site, regions surrounding the fusion peptide, and another allosteric site known to bind heme and biliverdin. The networks identified here highlight the complexity of the allosteric modulation in this protein and reveal a striking and unexpected connection between different allosteric sites. Notably, 65% of amino acid substitutions, deletions and insertions in the Alpha, Beta, Delta, Gamma and Omicron variants map onto or close to the identified allosteric pathways. Comparison of the FA site connections from D-NEMD in the glycosylated and non-glycosylated spikes revealed that the presence of glycans does not qualitatively change the internal allosteric pathways within the protein, with some glycans facilitating the transmission of the structural changes within and between subunits. Significance statementThe spike protein is crucial for the SARS-CoV-2 virus, enabling the fusion of the viral and host cell membranes. This protein contains several allosteric sites, including a fatty acid binding site at the interface between every two neighbouring receptor-binding domains. This site modulates the behaviour of the protein, with the binding of various free fatty acids and other small molecules influencing the spikes structure. In particular, the binding of linoleic acid, an essential fatty acid molecule, stabilizes the protein in a non-infectious locked conformation, thus making it inaccessible for binding to human receptors. Here, we investigate how the fatty acid site modulates the structural and dynamical behaviour of the fully glycosylated protein. Our work reveals complex patterns of communication between the fatty acid site and functionally important regions of the spike (including the receptor binding motif, the antigenic supersite in the N-terminal domain, the heme/biliverdin site, furin cleavage site and the fusion-peptide surrounding regions) and shed new light on the roles of glycans in this protein.

biochemistry↗

bioRxiv2023

Simulation-Driven Design of Stabilized SARS-CoV-2 Spike S2 Immunogens

The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, S2s usage as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimers opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Informed by molecular simulations and corroborated by experiments, we report an engineered S2 immunogen that exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.

biophysics↗

bioRxiv2023

Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE

Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and mucin-domain containing family of proteins (TIM-1, -3, -4) decorate immune cells and act as key checkpoint inhibitors in cancer. However, their dense O-glycosylation remains enigmatic both in terms of glycoproteomic landscape and structural dynamics, primarily due to the challenges associated with studying mucin domains. Here, we present a mucinase (SmE) and demonstrate its ability to selectively cleave along the mucin glycoprotein backbone, similar to others of its kind. Unlike other mucinases, though, SmE harbors the unique ability to cleave at residues bearing extremely complex glycans which enabled improved mass spectrometric analysis of several mucins, including the entire TIM family. With this information in-hand, we performed molecular dynamics (MD) simulations of TIM-3 and -4 to demonstrate how glycosylation affects structural features of these proteins. Overall, we present a powerful workflow to better understand the detailed molecular structures of the mucinome.

cancer biology↗

bioRxiv2022

Selectivity and ranking of tight-binding JAK-STAT inhibitors using Markovian milestoning with Voronoi tessellations

Janus kinases (JAK) are a group of proteins in the non-receptor tyrosine kinase (NRTKs) family that play a crucial role in growth, survival, and angiogenesis. They are activated by cytokines through the Janus kinase - signal transducer and activator of transcription (JAK-STAT) signaling pathway. JAK-STAT signaling pathways have significant roles in the regulation of cell division, apoptosis, and immunity. Identification of the V617F mutation in the Janus homology 2 (JH2) domain of JAK2 leading to myeloproliferative disorders has stimulated great interest in the drug discovery community to develop JAK2-specific inhibitors. However, such inhibitors should be selective towards JAK2 over other JAKs and display an extended residence time. Recently, novel JAK2/STAT5 axis inhibitors (N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives) have displayed extended residence times (hours or longer) on target and adequate selectivity excluding JAK3. To facilitate a deeper understanding of the kinase-inhibitor interactions and advance the development of such inhibitors, we utilize a multiscale Markovian milestoning with Voronoi tessellations (MMVT) approach within the Simulation-Enabled Estimation of Kinetic Rates v.2 (SEEKR2) program to rank-order these inhibitors based on their kinetic properties and further explain the selectivity of JAK2 inhibitors over JAK3. Our approach investigates the kinetic and thermodynamic properties of JAK-inhibitor complexes in a user-friendly, fast, efficient, and accurate manner compared to other brute force and hybrid enhanced sampling approaches.

biophysics↗

bioRxiv2022

Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors

Vaccines and drugs have helped reduce disease severity and blunt the spread of SARS-CoV-2. However, ongoing virus transmission, continuous evolution, and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease (Mpro/3CLpro) of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different resistance mutation profile. Importantly, phylogenetic analyses indicate that several of these resistant variants have pre-existed the introduction of these drugs into the human population and are capable of spreading. These results encourage the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy. One Sentence SummaryResistance to protease inhibitor drugs, nirmatrelvir (Paxlovid) and ensitrelvir (Xocova), exists in SARS-CoV-2 variants in the human population.

microbiology↗

bioRxiv2022

Breathing and Tilting: Mesoscale simulations illuminate influenza glycoprotein vulnerabilities

Influenza virus has resurfaced recently from inactivity during the early stages of the COVID-19 pandemic, raising serious concerns about the nature and magnitude of future epidemics. The main antigenic targets of influenza virus are two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Whereas the structural and dynamical properties of both glycoproteins have been studied previously, the understanding of their plasticity in the whole-virion context is fragmented. Here, we investigate the dynamics of influenza glycoproteins in a crowded protein environment through mesoscale all-atom molecular dynamics simulations of two evolutionary-linked glycosylated influenza A whole-virion models. Our simulations reveal and kinetically characterize three main molecular motions of influenza glycoproteins: NA head tilting, HA ectodomain tilting, and HA head breathing. The flexibility of HA and NA highlights antigenically relevant conformational states, as well as facilitates the characterization of a novel monoclonal antibody, derived from human convalescent plasma, that binds to the underside of the NA head. Our work provides previously unappreciated views on the dynamics of HA and NA, advancing the understanding of their interplay and suggesting possible strategies for the design of future vaccines and antivirals against influenza. One-Sentence SummaryIn situ dynamics of influenza glycoproteins expose antigenically relevant states and a new site of vulnerability in neuraminidase.

biophysics↗

bioRxiv2022

Targeting N-Myc in Neuroblastoma with Selective Aurora Kinase A Degraders

Summary ParagraphMYCN amplification is the most frequent genetic driver in high-risk neuroblastoma (NB) and strongly associated with poor prognosis.1,2 The N-Myc transcription factor, which is encoded by MYCN, is a mechanistically validated, yet challenging target for NB therapy development.3,4 In normal neuronal progenitors, N-Myc undergoes rapid degradation, while in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels.5,6 Allosteric Aurora-A inhibitors that displace N-Myc from binding can promote N-Myc degradation, but with limited efficacy.7-10 Here, we report a chemical approach to decrease N-Myc levels through the targeted protein degradation of Aurora-A. A first-in-class Aurora-A/N-Myc degrader, HLB-0532259 (compound 4), was developed from a novel Aurora-A-binding ligand that engages the Aurora-A/N-Myc complex. HLB-0532259 promotes the degradation of both Aurora-A and N-Myc with nanomolar potency and excellent selectivity and surpasses the cellular efficacy of established allosteric Aurora-A inhibitors. HLB-0532259 exhibits favorable pharmacokinetics properties and elicits tumor reduction in murine xenograft NB models. More broadly, this study delineates a novel strategy for targeting "undruggable" proteins that are reliant on accessory proteins for cellular stabilization.

cancer biology↗

bioRxiv2022

Targeted protein S-nitrosylation of ACE2 as potential treatment to prevent spread of SARS-CoV-2 infection

Prevention of infection and propagation of SARS-CoV-2 is of high priority in the COVID-19 pandemic. Here, we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 Spike protein, thereby inhibiting viral entry, infectivity, and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and thus spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E-protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model, and thus provide a novel avenue for therapy.

microbiology↗

bioRxiv2022

Architecture and self-assembly of the jumbo bacteriophage nuclear shell

Bacteria encode myriad defenses that target the genomes of infecting bacteriophage, including restriction-modification and CRISPR/Cas systems. In response, one family of large bacteriophage employs a nucleus-like compartment to protect their replicating genomes by excluding host defense factors. However, the principle composition and structure of this compartment remain unknown. Here, we find that the bacteriophage nuclear shell assembles primarily from one protein, termed chimallin. Combining cryo-electron tomography of nuclear shells in bacteriophage-infected cells and cryo-electron microscopy of a minimal chimallin compartment in vitro, we show that chimallin cooperatively self-assembles as a flexible sheet into closed micron-scale compartments. The architecture and assembly dynamics of the chimallin shell suggest mechanisms for its nucleation and growth, and its role as a scaffold for phage-encoded factors mediating macromolecular transport, cytoskeletal interactions, and viral maturation.

biophysics↗

bioRxiv2021

Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion function for retrotranslocation of ER multi-spanning membrane substrates

Nearly one-third of proteins are initially targeted to the endoplasmic reticulum (ER) membrane where they are correctly folded, assembled, and then delivered to their final cellular destinations. In order to prevent the accumulation of misfolded membrane proteins, ER associated degradation (ERAD) moves these clients from the ER membrane to the cytosol; a process known as retrotranslocation. Our recent work in S. cerevisiae has revealed a derlin rhomboid pseudoprotease, Dfm1, is involved in the retrotranslocation of ubiquitinated ERAD membrane substrates. In this study, we sought to understand the mechanism associated with Dfm1s actions and found that Dfm1s conserved rhomboid residues are critical for membrane protein retrotranslocation. Specifically, we identified several retrotranslocation-deficient Loop 1 mutants that display impaired binding to membrane substrates. Furthermore, Dfm1 has retained the lipid thinning functions of its rhomboid protease predecessors to facilitate in the removal of ER membrane substrates. We find this substrate engagement and lipid thinning feature is conserved in its human homolog, Derlin-1. Utilizing interaction studies and molecular dynamics simulations, this work reveals that derlin rhomboid pseudoproteases employ novel mechanisms of substrate engagement and lipid thinning for catalyzing extraction of multi-spanning membrane substrates.

cell biology↗

bioRxiv2021

Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN

High-fidelity replication of the large RNA genome of coronaviruses (CoVs) is mediated by a 3'-to-5' exoribonuclease (ExoN) in non-structural protein 14 (nsp14), which excises nucleotides including antiviral drugs mis-incorporated by the low-fidelity viral RNA-dependent RNA polymerase (RdRp) and has also been implicated in viral RNA recombination and resistance to innate immunity. Here we determined a 1.6-[A] resolution crystal structure of SARS-CoV-2 ExoN in complex with its essential co-factor, nsp10. The structure shows a highly basic and concave surface flanking the active site, comprising several Lys residues of nsp14 and the N-terminal amino group of nsp10. Modeling suggests that this basic patch binds to the template strand of double-stranded RNA substrates to position the 3' end of the nascent strand in the ExoN active site, which is corroborated by mutational and computational analyses. Molecular dynamics simulations further show remarkable flexibility of multi-domain nsp14 and suggest that nsp10 stabilizes ExoN for substrate RNA-binding to support its exoribonuclease activity. Our high-resolution structure of the SARS-CoV-2 ExoN-nsp10 complex serves as a platform for future development of anti-coronaviral drugs or strategies to attenuate the viral virulence.

biochemistry↗

bioRxiv2021

Independent Markov Decomposition: Towards modeling kinetics of biomolecular complexes

In order to advance the mission of in silico cell biology, modeling the interactions of large and complex biological systems becomes increasingly relevant. The combination of molecular dynamics (MD) and Markov state models (MSMs) have enabled the construction of simplified models of molecular kinetics on long timescales. Despite its success, this approach is inherently limited by the size of the molecular system. With increasing size of macromolecular complexes, the number of independent or weakly coupled subsystems increases, and the number of global system states increase exponentially, making the sampling of all distinct global states unfeasible. In this work, we present a technique called Independent Markov Decomposition (IMD) that leverages weak coupling between subsystems in order to compute a global kinetic model without requiring to sample all combinatorial states of subsystems. We give a theoretical basis for IMD and propose an approach for finding and validating such a decomposition. Using empirical few-state MSMs of ion channel models that are well established in electrophysiology, we demonstrate that IMD can reproduce experimental conductance measurements with a major reduction in sampling compared with a standard MSM approach. We further show how to find the optimal partition of all-atom protein simulations into weakly coupled subunits. Significance StatementMolecular simulations of proteins are often interpreted using Markov state models (MSMs), in which each protein configuration is assigned to a global state. As we explore larger and more complex biological systems, the size of this global state space will face a combinatorial explosion, rendering it impossible to gather sufficient sampling data. In this work, we introduce an approach to decompose a system of interest into separable subsystems. We show that MSMs built for each subsystem can be later coupled to reproduce the behaviors of the global system. To aid in the choice of decomposition we also describe a score to quantify its goodness. This decomposition strategy has the promise to enable robust modeling of complex biomolecular systems.

biophysics↗

bioRxiv2021

A glycan gate controls opening of the SARS-CoV-2 spike protein

SARS-CoV-2 infection is controlled by the opening of the spike protein receptor binding domain (RBD), which transitions from a glycan-shielded "down" to an exposed "up" state in order to bind the human ACE2 receptor and infect cells. While snapshots of the "up" and "down" states have been obtained by cryoEM and cryoET, details of the RBD opening transition evade experimental characterization. Here, over 130 s of weighted ensemble (WE) simulations of the fully glycosylated spike ectodomain allow us to characterize more than 300 continuous, kinetically unbiased RBD opening pathways. Together with ManifoldEM analysis of cryo-EM data and biolayer interferometry experiments, we reveal a gating role for the N-glycan at position N343, which facilitates RBD opening. Residues D405, R408, and D427 also participate. The atomic-level characterization of the glycosylated spike activation mechanism provided herein achieves a new high-water mark for ensemble pathway simulations and offers a foundation for understanding the fundamental mechanisms of SARS-CoV-2 viral entry and infection.

biophysics↗

bioRxiv2021

Discovery of an IKK2 Site that Allosterically Controls Its Activation

I{kappa}B kinase 2/{beta} (IKK2) is a critical regulator of inflammation which is inducibly activated by a host of stimuli. Aberrant activation of IKK2 is the leading cause of most inflammatory diseases and many associated cancers. Efforts to prevent these diseases by small-molecule inhibitors of IKK2 activity have not been successful. Most inhibitors developed for IKK2 are ATP-competitive, and they are toxic in vivo due to their off-target effects. Here we focused on identifying inhibitors to block IKK2 activity from an allosteric site, not the ATP-binding pocket. Using virtual screening, we first identified several candidate allosteric sites and screened for potential small-molecule binders, and then selected candidates inhibitory to IKK2 activity using cell-based functional assays. Hydrogen deuterium exchange coupled to mass-spectrometry (HDX-MS) and MS-MS assays revealed that a class of benzoyl conjugates of pyrrolidinedione covalently bound to a site located at the interface of the kinase domain (KD) and the helical domain (SDD), and inhibited IKK2 activation allosterically by preventing phosphorylation of its activation loop serines. Additionally, this class of inhibitor partially blocks IKK2s catalytic activity by enhancing dynamics within the ATP binding pocket and likely the general active site. Hydrogen deuterium exchange (HDX) experiments further revealed that while binding of substrate ATP perturbs only the local structure surrounding its binding site, binding to ATP-competitive or allosteric inhibitors induces structural perturbations in an expansive area including the helical domain. We propose that these allosteric sites can act as specific targets for the development of novel potent IKK inhibitors. SIGNIFICANCEAberrant activation of IKK2 is the leading cause of most inflammatory diseases and many associated cancers. Most inhibitors developed for IKK2 are ATP-competitive, and they are toxic in vivo due to their off-target effects. By combination of virtual screening and cell-based functional assays, we identified small-molecule binders of the class of benzoyl conjugates of pyrrolidinedione that block IKK2 activity from an allosteric site through covalent attachment and could be specific only for IKK2. HDX-MS and MS-MS assays identified a binding pocket with a Cys-Cys motif for these inhibitors, and revealed specific differences in IKK2 dynamics upon binding to substrate ATP vs ATP-competitive and allosteric inhibitors. Present work provides a framework for the development of allosteric inhibitors to combat IKK2-induced diseases inhibitors.

biochemistry↗

bioRxiv2020

SARS-CoV-2 escape in vitro from a highly neutralizing COVID-19 convalescent plasma

To investigate the evolution of SARS-CoV-2 in the immune population, we co-incubated authentic virus with a highly neutralizing plasma from a COVID-19 convalescent patient. The plasma fully neutralized the virus for 7 passages, but after 45 days, the deletion of F140 in the spike N-terminal domain (NTD) N3 loop led to partial breakthrough. At day 73, an E484K substitution in the receptor-binding domain (RBD) occurred, followed at day 80 by an insertion in the NTD N5 loop containing a new glycan sequon, which generated a variant completely resistant to plasma neutralization. Computational modeling predicts that the deletion and insertion in loops N3 and N5 prevent binding of neutralizing antibodies. The recent emergence in the United Kingdom and South Africa of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed. One Sentence SummaryThree mutations allowed SARS-CoV-2 to evade the polyclonal antibody response of a highly neutralizing COVID-19 convalescent plasma.

immunology↗

bioRxiv2020

Disease related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveals a path to selective inhibitors

Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the p110{gamma} subunit playing a key role in immune signalling. PI3K{gamma} is a key factor in inflammatory diseases, and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the c-terminus can inactivate or activate enzyme activity. Screening of small molecule inhibitors using HDX-MS revealed that activation loop binding inhibitors induce allosteric conformational changes that mimic those seen for the R1021C mutant. Structural analysis of clinically advanced PI3K inhibitors revealed novel binding pockets that can be exploited for further therapeutic development. Overall this work provides unique insight into the regulatory mechanisms that control PI3K{gamma} kinase activity, and shows a framework for the design of PI3K isoform and mutant selective inhibitors.

biochemistry↗

bioRxiv2020

AI-Driven Multiscale Simulations Illuminate Mechanisms of SARS-CoV-2 Spike Dynamics

We develop a generalizable AI-driven workflow that leverages heterogeneous HPC resources to explore the time-dependent dynamics of molecular systems. We use this workflow to investigate the mechanisms of infectivity of the SARS-CoV-2 spike protein, the main viral infection machinery. Our workflow enables more efficient investigation of spike dynamics in a variety of complex environments, including within a complete SARS-CoV-2 viral envelope simulation, which contains 305 million atoms and shows strong scaling on ORNL Summit using NAMD. We present several novel scientific discoveries, including the elucidation of the spikes full glycan shield, the role of spike glycans in modulating the infectivity of the virus, and the characterization of the flexible interactions between the spike and the human ACE2 receptor. We also demonstrate how AI can accelerate conformational sampling across different systems and pave the way for the future application of such methods to additional studies in SARS-CoV-2 and other molecular systems. ACM Reference FormatLorenzo Casalino1{dagger}, Abigail Dommer1{dagger}, Zied Gaieb1{dagger}, Emilia P. Barros1, Terra Sztain1, Surl-Hee Ahn1, Anda Trifan2,3, Alexander Brace2, Anthony Bogetti4, Heng Ma2, Hyungro Lee5, Matteo Turilli5, Syma Khalid6, Lillian Chong4, Carlos Simmerling7, David J. Hardy3, Julio D. C. Maia3, James C. Phillips3, Thorsten Kurth8, Abraham Stern8, Lei Huang9, John McCalpin9, Mahidhar Tatineni10, Tom Gibbs8, John E. Stone3, Shantenu Jha5, Arvind Ramanathan2*, Rommie E. Amaro1*. 2020. AI-Driven Multiscale Simulations Illuminate Mechanisms of SARS-CoV-2 Spike Dynamics. In Supercomputing 20: International Conference for High Performance Computing, Networking, Storage, and Analysis. ACM, New York, NY, USA, 14 pages. https://doi.org/finalDOI

biophysics↗