Biology subjects

Sauve, S.

Publications and source records attributed to Sauve, S..

6 recordsLinked to original sources

bioRxiv2026

Free-Energy and Molecular Dynamics Analysis of Ser195 and Thr195 Rotameric States in Thrombin

Ser195 is highly conserved as the catalytic nucleophile in trypsin like serine proteases, yet the molecular basis for the strong preference for serine over the chemically similar threonine residue remains unclear. Here, we used well tempered metadynamics and microsecond long molecular dynamics (MD) simulations to characterize the conformational energetics of S195 and T195 in thrombin. Well tempered metadynamics revealed distinct rotameric free energy landscapes in both the apo and the ligand bound systems. In the apo state, S195 preferentially occupied a lower angle rotameric state, while T195 exhibited two low energy states with similar free energies. Unbiased simulations further showed greater conformational heterogeneity and increased higher angle sampling for T195. Evaluation of the His57 to residue 195 hydrogen bond further revealed that S195 maintained close hydrogen bond distances across both rotameric regions, whereas T195 exhibited longer and more variable His57 to hydroxyl distances with reduced distance based occupancy. Analysis of the local environment showed that the additional T195 methyl group was associated with redistributed protein contacts. Additional rotamer conditioned analyses demonstrated differences in local packing within corresponding conformational states. Furthermore, solvent accessibility and water contact analyses revealed that the effects of the substitution on the catalytic side chain environment depend on rotameric conformation. Together, these findings demonstrate that two complementary simulation approaches converge on similar conformational preferences and suggest that the S195T substitution alters the rotameric free energy landscape in association with changes in catalytic geometry, local packing, and solvation. These results provide insight into the evolutionary preference for serine over threonine at the catalytic position of thrombin.

biophysics↗

bioRxiv2026

Differential Behavior of Uncleaved gp160 Human Immunodeficiency Virus Type 1 (HIV-1) Envelope (Env) Glycoproteins

The envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) plays important roles in viral entry by coordinating host-cell receptor recognition and membrane fusion. Env is synthesized as a homotrimeric precursor, gp160, which is cleaved into gp120 and gp41 subunits. Although the cleaved form of Env is required for fusion, uncleaved Env remains plentiful on the surface of HIV-1-infected cells. Previous studies have suggested that uncleaved Env is conformationally more flexible than the cleaved form making its dynamics important for understanding the broader structural landscape of HIV-1 Env. In this study, we employed microsecond-long all-atom molecular dynamics (MD) simulations to characterize the dynamics of two structures of uncleaved HIV-1 Env that have been previously assigned to the same conformational state. Our results reveal differences in their conformational behavior, including differences in collective motions, FRET distributions, and trimer symmetry. These findings provide molecular-level insight into the structural plasticity of uncleaved HIV-1 Env and highlight that different structures within the same conformational state can exhibit distinct dynamic behavior.

biophysics↗

bioRxiv2026

Predicting Binding Affinities for the Binding Domain of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Isoforms Using Free-Energy Perturbation

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are are a family of voltage-gated, cyclic-nucleotide modulated Na+/K+ channels that regulate spontaneous rhythmic electrical activity in both the heart and the brain. Understanding differences in the responsiveness to cyclic adenosine monophosphate (cAMP) modulation between HCN isoforms would offer insight into the specific binding interactions that drive channel activation. Using all-atom molecular dynamics (MD) simulations and the free-energy perturbation (FEP) approach, we determined the absolute binding free energy of cAMP to the the cyclicnucleotide-binding domain (CNBD) of HCN isoforms 1-4. By studying the free-energy of ligand binding to the various isoforms of HCN, our study advances the understanding of HCN channel activation and modulation mechanisms. Overall, our work offers insight into explaining differences in channel sensitivity across the isoforms of HCN.

biophysics↗

bioRxiv2026

Linking Cyanobacterial Genomes to Toxin Dynamics Through Genome-Resolved Metagenomics

Global climate change and nutrient pollution from agricultural systems increase cyanobacterial bloom and toxin release events, and will pose a significant concern for public health and safety over the coming decades. Many in situ studies have focused on environmental, chemical, and microbial community changes and their impact on cyanobacterial bloom frequency and toxicity. However, fine-scale genetic differences in the genomes of bloom-forming cyanobacteria may also impact the quantity and types of toxins produced. Metagenomic approaches allow resolution of strain- and nucleotide-level changes within microbial communities and can improve our understanding of the factors that affect cyanobacterial bloom dynamics and toxicity. Here, we conduct a metagenomic analysis of the bloom-forming cyanobacterial genus Microcystis across a 10-month lake time series from the Valle de Bravo Reservoir, to assess how within-genus genotype-level changes are linked to intracellular toxin production and extracellular toxin release, as well as how single nucleotide variation may affect the types of microcystin toxins produced. Our results demonstrate that the abundances of both toxigenic and non-toxigenic Microcystis genotypes are significantly related to microcystin toxin concentrations. In addition to these genome-wide ("strain"-level) associations, specific single nucleotide variants show strong associations with chemical variants of microcystin in the environment. Our work highlights the importance of fine-scale analysis of microbial community composition for understanding cyanobacterial bloom dynamics and toxin production.

microbiology↗

bioRxiv2025

Durability of DNA-LNP and mRNA-LNP Vaccine-Induced Immunity Against SARS-CoV-2 XBB.1.5

mRNA-lipid nanoparticle (LNP) vaccines induce robust adaptive immune responses and have proven highly effective against SARS-CoV-2. However, their long-term effectiveness is limited by waning humoral responses, which decline substantially within the first six months post-boost vaccination. DNA-LNPs are being investigated as an alternative vaccine platform, offering prolonged antigen expression and robust immunity. Here, we present the first comparison of SARS-CoV-2 DNA- and mRNA-LNP vaccines in a long-term in vivo challenge model. Both nucleic acid platforms induced strong neutralizing antibody responses and conferred equivalent protection in Syrian hamsters challenged three weeks post-boost. Notably, DNA-LNP vaccination maintained high binding and neutralizing antibody titers six months post-boost, whereas mRNA-LNPs exhibited a marked decline. Correspondingly, while DNA-LNPs completely protected from weight loss, viral replication, and lung pathology at this late timepoint, mRNA-LNP vaccination conferred minimal protection. These findings demonstrate that DNA-LNPs can sustain durable immunity, highlighting their potential as a next-generation vaccine platform that could reduce the need for frequent boosters.

immunology↗

bioRxiv2019

Extreme midsummer rainfall event drives early onset cyanobacterial bloom

O_LIThe increasing prevalence of cyanobacteria-dominated harmful algal blooms is strongly associated with nutrient loading and changing climatic patterns. Changes to precipitation frequency and intensity, as predicted by current climate models, are likely to affect bloom development and composition through changes in nutrient fluxes and water column mixing. However, few studies have directly documented the effects of extreme precipitation events on cyanobacterial composition, biomass, and toxin production. C_LIO_LIWe tracked changes in a eutrophic reservoir following an extreme precipitation event, describing an atypically early toxin-producing cyanobacterial bloom, successional progression of the phytoplankton community, toxins, and geochemistry. C_LIO_LIAn increase in bioavailable phosphorus by more than 27-fold in surface waters preceded notable increases in Aphanizomenon flos-aquae throughout the reservoir approximately 2 weeks post flood and ~5 weeks before blooms typically occur. Anabaenopeptin-A and three microcystin congeners (microcystin-LR, -YR, and -RR) were detected at varying levels across sites during the bloom period, which lasted between 3 and 5 weeks. C_LIO_LISynthesis and applications: These findings suggest extreme rainfall can trigger early cyanobacterial bloom initiation, effectively elongating the bloom season period of potential toxicity. However, effects will vary depending on factors including the timing of rainfall and reservoir physical structure. In contrast to the effects of early season extreme rainfall, a mid-summer runoff event appeared to help mitigate the bloom in some areas of the reservoir by increasing flushing. C_LI

ecology↗