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biorxiv; 2021.
Preprint Dans Anglais | bioRxiv | ID: ppzbmed-10.1101.2021.12.02.470852


SARS-CoV2 spike glycoprotein is prime target for vaccines and for diagnostics and therapeutic antibodies against the virus. While anchored in the viral envelope, for effective virulence, the spike needs to maintain structural flexibility to recognize the host cell surface receptors and bind to them, a property that can heavily hinge upon the dynamics of the unresolved domains, most prominently the stalk. Construction of the complete, membrane-bound spike model and the description of its dynamics remain critical steps in understanding the inner working of this key element in viral infection. Using a hybrid approach, combining homology modeling, protein-protein docking and MD simulations, guided by biochemical and glycomics data, we have developed a full-length, membrane-bound, palmitoylated and fully-glycosylated spike structure in a native membrane. Multi-microsecond MD simulations of this model, the longest known trajectory of the full-spike, reveals conformational dynamics employed by the protein to explore the crowded surface of the host cell. In agreement with cryoEM, three flexible hinges in stalk allow for global conformational heterogeneity of spike in the fully-glycosyslated system mediated by glycan-glycan and glycan-lipid interactions. Dynamical range of spike is considerably reduced in its non-glycosylated form, confining the area explored by the spike on the host cell surface. Furthermore, palmitoylation of the membrane domain amplify the local curvature that may prime the fusion. We show that the identified hinge regions are highly conserved in SARS coronaviruses, highlighting their functional importance in enhancing viral infection, and thereby provide novel points for discovery of alternative therapeutics against the virus.

biorxiv; 2021.
Preprint Dans Anglais | bioRxiv | ID: ppzbmed-10.1101.2021.10.09.463779


The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication transcription complex (RTC) is a multi-domain protein responsible for replicating and transcribing the viral mRNA inside a human cell. Attacking RTC function with pharmaceutical compounds is a pathway to treating COVID-19. Conventional tools, e.g., cryo-electron microscopy and all-atom molecular dynamics (AAMD), do not provide sufficiently high resolution or timescale to capture important dynamics of this molecular machine. Consequently, we develop an innovative workflow that bridges the gap between these resolutions, using mesoscale fluctuating finite element analysis (FFEA) continuum simulations and a hierarchy of AI-methods that continually learn and infer features for maintaining consistency between AAMD and FFEA simulations. We leverage a multi-site distributed workflow manager to orchestrate AI, FFEA, and AAMD jobs, providing optimal resource utilization across HPC centers. Our study provides unprecedented access to study the SARS-CoV-2 RTC machinery, while providing general capability for AI-enabled multi-resolution simulations at scale.

biorxiv; 2020.
Preprint Dans Anglais | bioRxiv | ID: ppzbmed-10.1101.2020.10.27.357350


Infection of human cells by the SARS-CoV2 relies on its binding to a specific receptor and subsequent fusion of the viral and host cell membranes. The fusion peptide (FP), a short peptide segment in the spike protein, plays a central role in the initial penetration of the virus into the host cell membrane, followed by the fusion of the two membranes. Here, we use an array of molecular dynamics (MD) simulations taking advantage of the Highly Mobile Membrane Mimetic (HMMM) model, to investigate the interaction of the SARS-CoV2 FP with a lipid bilayer representing mammalian cellular membranes at an atomic level, and to characterize the membrane-bound form of the peptide. Six independent systems were generated by changing the initial positioning and orientation of the FP with respect to the membrane, and each system was simulated in five independent replicas. In 60% of the simulations, the FP reaches a stable, membrane-bound configuration where the peptide deeply penetrated into the membrane. Clustering of the results reveals two major membrane binding modes, the helix-binding mode and the loop-binding mode. Taken into account the sequence conservation among the viral FPs and the results of mutagenesis studies establishing the role of specific residues in the helical portion of the FP in membrane association, we propose that the helix-binding mode represents more closely the biologically relevant form. In the helix-binding mode, the helix is stabilized in an oblique angle with respect to the membrane with its N-terminus tilted towards the membrane core. Analysis of the FP-lipid interactions shows the involvement of specific residues of the helix in membrane binding previously described as the fusion active core residues. Taken together, the results shed light on a key step involved in SARS-CoV2 infection with potential implications in designing novel inhibitors.

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