Biology subjects

Kearns, F.

Publications and source records attributed to Kearns, F..

5 recordsLinked to original sources

bioRxiv2026

Condensate-Like Organization in Respiratory Aerosols Modulates the Dynamics of an Airborne Virus

The molecular behavior of viruses within respiratory aerosols plays a critical role in airborne disease transmission yet remains largely inaccessible to experimental characterization. Here, we use a billion-atom all-atom molecular dynamics simulation of a virus-laden respiratory aerosol to uncover how respiratory proteins, lipids, ions, and water collectively assemble around SARS-CoV-2, giving rise to structured microenvironments that influence viral stability and spike dynamics. We find that respiratory components rapidly evolve into heterogeneous networks characterized by protein-rich aggregates, patchy lipid assemblies, and spatially structured ion and water dynamics. These features create distinct microenvironments that constrain molecular transport and stabilize regions surrounding the virion. Within this crowded aerosol context, we observe sustained and selective interactions between aerosol components and the viral spike protein, including preferential recruitment of surfactant lipids and persistent coordination by divalent cations. These interactions modulate spike conformational dynamics, enhancing domain breathing motions and flexibility at key hinge regions while preserving a stable membrane anchor. Together, these observations reveal a condensate-like physical regime in which multivalent aerosol components coalesce into a soft, heterogeneous matrix that selectively modulates viral protein dynamics under extreme crowding. By framing virus-laden respiratory aerosols within this physical context, this work establishes an in situ molecular framework for understanding how aerosols influence viral persistence and offers a platform for exploring mechanisms relevant to airborne disease transmission and mitigation strategies. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/721971v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@4d0f60org.highwire.dtl.DTLVardef@12c9d1forg.highwire.dtl.DTLVardef@1ff6c29org.highwire.dtl.DTLVardef@15feec_HPS_FORMAT_FIGEXP M_FIG C_FIG SynopsisRespiratory aerosols exhibit condensate-like physical properties that govern the evolution of the particle and modulate the behavior of airborne SARS-CoV-2.

biophysics↗

bioRxiv2025

Structural Dynamics and Allosteric Communication of a SARS-Like Bat Coronavirus Spike Glycoprotein

SARS-like bat coronaviruses (CoVs) pose ongoing public health risks due to their zoonotic potential, making it important to understand the molecular pathways driving their evolution. We recently showed that SHC014-CoV can infect human cell lines in an ACE2-dependent manner after acquiring two spike ectodomain mutations (F294L and A835D). However, how the wild-type (WT) SHC014 spike differs dynamically from these mutants remains unclear. Here, we built fully glycosylated ectodomain models of WT and three mutants (F294L, A835D, and the double mutant, DM) and performed triplicate 1-s all-atom molecular dynamics (MD) simulations for each variant. The two mutations exhibit epistasis, altering structural rearrangements relative to WT. Notably, the DM receptor binding domain (RBD) begins sampling the open conformation in our conventional MD. At the atomic level, the DM spike mitigates the dense negative packing introduced by A835D through a salt-bridge network, while F294L disrupts {pi}-mediated interactions, together enhancing RBD opening propensity--critical for viral entry. Increased flexibility of the subdomain-2 "620-loop" further modulates DM RBD openness. Dynamical network analysis identified three allosteric communication pathways. In WT and F294L, "Pathway 1" forms the baseline route linking the 620-loop to the RBD, whereas in A835D and DM it extends to the FPPR, reshaping long-range communication. "Pathway 2" is conserved across variants but is most prominent in WT and F294L. "Pathway 3" appears only in A835D and DM, compensating for reduced communication along Pathway 2. Overall, this work provides an atomistic perspective on SHC014 molecular adaptation during host-to-host transmission and highlights mechanistic features that may inform future therapeutic and pandemic-preparedness efforts. Statement of SignificanceBat coronaviruses are an important source of future pandemic threats, but we still know little about how small genetic changes help them infect humans. In this study, we used detailed computer simulations to watch how tiny mutations in a bat coronavirus spike protein change its motion and shape. We found that two specific mutations work together to make the spike more likely to open--a step required for the virus to enter human cells. By revealing how these molecular changes increase infection potential, our work helps improve understanding of coronavirus evolution and may guide strategies to prepare for future outbreaks.

biophysics↗

bioRxiv2025

D614G reshapes allosteric networks and opening mechanisms of SARS-CoV-2 spikes

The SARS-CoV-2 spike glycoprotein binds human epithelial cells and enables infection through a key conformational transition that exposes its receptor binding domain (RBD). Experimental evidence indicates that spike mutations, particularly the early D614G variant, alter the rate of this conformational shift, potentially increasing viral infectivity. To investigate how mutations reshape the conformational landscape, we conducted extensive weighted ensemble simulations of the Ancestral, Delta, and Omicron BA.1 spike strains along the RBD opening pathway. We observe that Ancestral, Delta, and Omicron BA.1 spike RBDs open differently, with Omicron BA.1 following a more direct opening profile until it reaches a "super-open" state wherein it begins to "peel", suggesting increased S1 flexibility. Via dynamical network analysis, we identified two allosteric communication networks uniting all S1 domains: the established N2R linker and a newly discovered anti-parallel R2N linker. In Delta and Omicron BA.1 variant spikes, RBD opening is facilitated by both linkers, while the Ancestral strain relies predominantly on the N2R linker. In the ancestral spike, the D614-K854 salt bridge impedes allosteric communication through the R2N linker, whereas the loss of this salt bridge in all subsequent VOCs alleviates local frustration and, we believe, accelerates RBD opening. Hydrogen-deuterium mass spectrometry experiments validate these altered dynamics in the D614 region across Ancestral, D614G, and Omicron BA.1 spikes. This study unveils a hidden allosteric network, connecting the NTD to the RBD via the 614-proximal region, and the D614G mutation reshapes the fitness landscape of these critical viral glycoproteins. Significance StatementOur work reveals how the D614G mutation in the SARS-CoV-2 spike protein reshapes its internal communication pathways and speeds up receptor binding domain (RBD) opening, providing mechanistic insight into the evolution and enhanced infectivity of SARS-CoV-2 variants of concern. We also describe differences in opening pathways and relative rates of opening for Delta and Omicron BA.1 spike RBDs relative to the original (Ancestral) coronavirus strain from Wuhan, China.

biophysics↗

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↗

bioRxiv2021

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

We seek to completely revise current models of airborne transmission of respiratory viruses by providing never-before-seen atomic-level views of the SARS-CoV-2 virus within a respiratory aerosol. Our work dramatically extends the capabilities of multiscale computational microscopy to address the significant gaps that exist in current experimental methods, which are limited in their ability to interrogate aerosols at the atomic/molecular level and thus ob-scure our understanding of airborne transmission. We demonstrate how our integrated data-driven platform provides a new way of exploring the composition, structure, and dynamics of aerosols and aerosolized viruses, while driving simulation method development along several important axes. We present a series of initial scientific discoveries for the SARS-CoV-2 Delta variant, noting that the full scientific impact of this work has yet to be realized. ACM Reference FormatAbigail Dommer1{dagger}, Lorenzo Casalino1{dagger}, Fiona Kearns1{dagger}, Mia Rosenfeld1, Nicholas Wauer1, Surl-Hee Ahn1, John Russo,2 Sofia Oliveira3, Clare Morris1, AnthonyBogetti4, AndaTrifan5,6, Alexander Brace5,7, TerraSztain1,8, Austin Clyde5,7, Heng Ma5, Chakra Chennubhotla4, Hyungro Lee9, Matteo Turilli9, Syma Khalid10, Teresa Tamayo-Mendoza11, Matthew Welborn11, Anders Christensen11, Daniel G. A. Smith11, Zhuoran Qiao12, Sai Krishna Sirumalla11, Michael OConnor11, Frederick Manby11, Anima Anandkumar12,13, David Hardy6, James Phillips6, Abraham Stern13, Josh Romero13, David Clark13, Mitchell Dorrell14, Tom Maiden14, Lei Huang15, John McCalpin15, Christo- pherWoods3, Alan Gray13, MattWilliams3, Bryan Barker16, HarindaRajapaksha16, Richard Pitts16, Tom Gibbs13, John Stone6, Daniel Zuckerman2*, Adrian Mulholland3*, Thomas MillerIII11,12*, ShantenuJha9*, Arvind Ramanathan5*, Lillian Chong4*, Rommie Amaro1*. 2021. #COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy ofDeltaSARS-CoV-2 in a Respiratory Aerosol. In Supercomputing 21: International Conference for High Perfor-mance Computing, Networking, Storage, and Analysis. ACM, New York, NY, USA, 14 pages. https://doi.org/finalDOI

biophysics↗