A5069698996- SARS-CoV-2 and COVID-19 Research
- Lipid Membrane Structure and Behavior
- Surfactants and Colloidal Systems
- vaccines and immunoinformatics approaches
- Advancements in Transdermal Drug Delivery
- Viral gastroenteritis research and epidemiology
- SARS-CoV-2 detection and testing
- Spectroscopy and Quantum Chemical Studies
- COVID-19 Clinical Research Studies
- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Bacteriophages and microbial interactions
- Animal Virus Infections Studies
- HIV/AIDS drug development and treatment
- COVID-19 Impact on Reproduction
- interferon and immune responses
- Viral Infections and Outbreaks Research
- Infection Control and Ventilation
- COVID-19 epidemiological studies
- HIV Research and Treatment
- Cell death mechanisms and regulation
- Endoplasmic Reticulum Stress and Disease
- Heat shock proteins research
- Computational and Text Analysis Methods
- Nanopore and Nanochannel Transport Studies
Massachusetts Institute of Technology
2022-2025
La Jolla Institute for Immunology
2021-2022
National Institutes of Health
2021
National Heart Lung and Blood Institute
2021
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2021
University of Maryland, College Park
2017-2020
University of Cambridge
2020
Yale University
2020
Duke University
2010
Permeation of many small molecules through lipid bilayers can be directly observed in molecular dynamics simulations on the nano- and microsecond timescale. While unbiased provide an unobstructed view permeation process, their feasibility for computing permeability coefficients depends various factors that differ each permeant. The present work studies three which are feasible within less than a microsecond, one hydrophobic (oxygen), hydrophilic (water), amphiphilic (ethanol). Permeabilities...
The all-atom CHARMM36 (C36) force field is used to simulate bilayers of pure palmitoylsphingomyelin (PSM) as well binary mixtures PSM and stearoylsphingomyelin (SSM) at various cholesterol concentrations (XC) temperatures. C36 simulation data in good agreement with experimental deuterium order parameters previous computational results, providing evidence the utility for potentially studying more complex membranes. area compressibility modulus shown achieve a large value 2.82 ± 0.08 N/m...
The barrier function of the stratum corneum (SC) is intimately related to structure lipid matrix, which composed ceramides (Cer), cholesterol (Chol), and free fatty acid (FFA). In this study, all-atom CHARMM36 (C36) force field used simulate bilayers N-palmitoylsphingosine (Cer16), N-lignoceroylsphingosine (Cer24), Chol, lignoceric (LA) as simple models SC. Equimolar mixtures Cer, LA are replicated from experiment for comparison validation C36 field, effects diversity temperature studied....
Nanoparticle vaccines displaying combinations of SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs) could protect against SARS-CoV-2 variants and spillover zoonotic sarbecoviruses into humans. Using a computational approach, we designed RBDs selected 7 natural sarbecovirus RBDs, each predicted to fold properly abrogate antibody responses variable epitopes. were attached 60-mer nanoparticles make immunogens two (mosaic-2COMs), five (mosaic-5COM), or seven (mosaic-7COM)...
SUMMARY Antiretroviral therapy (ART) inhibits Human Immunodeficiency Virus (HIV) replication to maintain undetectable viral loads in people living with HIV, but does not result a cure. Due the significant challenges of lifelong ART for many, there is strong interest therapeutic strategies that Recent clinical trials have shown administration broadly neutralizing antibodies (bnAbs) when some viremia can lead ART-free control people; however, underlying mechanisms are unclear. Our...
Significance Maintaining a functional cell requires the collaboration of large number biomolecules that regulate key biochemical processes. The p97 protein is essential in this effort, interacting with adaptor molecules target it to different regions for specific functions. Here, we study structural dynamics complex formed between and p47 critical membrane assembly. Our data establish p47–p97 interaction partly regulated by are intrinsically disordered, manner depends on whether adenosine...
1Using computational methods, we designed 60-mer nanoparticles displaying SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs) by (i) creating RBD sequences with 6 mutations in the SARS-COV-2 WA1 that were predicted to retain proper folding and abrogate antibody responses variable epitopes (mosaic-2COMs; mosaic-5COM), (ii) selecting 7 natural sarbecovirus RBDs (mosaic-7COM). These antigens compared mosaic-8b, which elicits cross-reactive antibodies protects from...
Recent studies in lipid raft formation and stratum corneum permeability have focused on the role of ceramides (CER). In this study, we use all-atom CHARMM36 (C36) force field to simulate bilayers using N-palmitoylsphingosine (CER16) or α-hydroxy-N-stearoyl phytosphingosine (CER[AP]) 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), which serve as general membrane models. Conditions are replicated from experimental for comparison purposes,...
Permeation of small molecules through membranes is a fundamental biological process, and molecular dynamics simulations have proven to be promising tool for studying the permeability by providing precise characterization free energy diffusivity. In this study, permeation ethanol three different 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (POPS), PO-phosphatidylethanolamine (POPE), PO-phosphatidylcholine (POPC) studied. Permeabilities are calculated compared with two approaches based...
The primary barrier of the skin is provided by outer layer known as stratum corneum, making it active target for transdermal drug delivery. A repeating structure SC short periodicity phase modeled a bilayer composed ceramides (Cer), cholesterol (Chol), and free fatty acids (FFA). This study simulates Cer/Chol/FFA bilayers N-lignoceroylsphingosine, α-lignoceroylphytosphingosine, Chol, deprotonated lignoceric acid, protonated acid using CHARMM36 force field to effects Cer concentration,...
The stratum corneum (SC), which functions as a barrier to many exogenous molecules, contains ceramides (Cer) in both bilayer and multilayer structures. Simple models of the SC using pure Cer lamellae are simulated studied CHARMM36 force field. For single bilayers, chain length is noted have significant effect on thickness interdigitation, whereas hydroxylation induces more prominent effects hydrogen bonding. CerEOS, due its long fatty acid tail (48 carbons), double layer that possesses...
The ability to predict antibody-antigen binding is essential for computational models of antibody affinity maturation and protein design. While most aim arbitrary antigens antibodies, the global impact SARS-CoV-2 on public health availability associated data suggest that a SARS-CoV-2-specific model would be highly beneficial. In this work, we present neural network model, trained ∼315 000 datapoints from deep mutational scanning experiments, predicts escape fractions RBDs antibodies....
The rise of SARS-CoV-2 variants and the history outbreaks caused by zoonotic coronaviruses point to need for next-generation vaccines that confer protection against variant strains. Here, we combined analyses diverse sequences structures coronavirus spikes with data from deep mutational scanning design antigens containing most significant mutations may emerge. We trained a neural network predict RBD expression ACE2 binding sequence, which allowed us determine these are stable bind ACE2....
Abstract Herein we measured CD4 + T cell responses against common cold corona (CCC) viruses and SARS-CoV-2 in high-risk health care workers (HCW) community controls. We observed higher levels of CCC reactive cells seronegative HCW compared to donors, consistent with potential occupational exposure CCC. further show that reactivity was than controls correlation between is cross-reactivity not associated recent vivo activation. Surprisingly, decreased infected HCW, suggesting might interfere...
Immune memory to Common Cold Coronaviruses (CCCs) influences SARS-CoV-2 infection outcome, and is crucial for pan-corona vaccine development. We performed a longitudinal analysis of pre-pandemic samples collected from 2016-2019, assessed CCC-specific CD4+ T cell antibody responses, comparing other respiratory viruses ubiquitous pathogens. Notably, CCC responses were detected in most subjects, with comparable frequencies as common antigens, sustained over time. associated low HLA-DR+CD38+...
Abstract The rise of SARS-CoV-2 variants and the history outbreaks caused by zoonotic coronaviruses point to need for next-generation vaccines that confer protection against variant strains. Here, we combined analyses diverse sequences structures coronavirus spikes with data from deep mutational scanning design antigens containing most significant mutations may emerge. We trained a neural network predict RBD expression ACE2 binding sequence, which allowed us determine these are stable bind...
All-atom models of the long periodicity phase (LPP) in stratum corneum (SC) are studied using bilayer–slab–bilayer (sandwich) structures and multi-microsecond simulations. Linoleate promotes melting interior slab, which contains ceramide (Cer) posturing chain conformation, a structurally distinct conformation from full extension. The mechanism Cer transitioning into extension is characterized by initial anchoring head-proximal carbons occurs over tens nanoseconds. Free fatty acids...
Abstract In response to the threat of emerging SARS-CoV-2 variants and SARS-like betacoronaviruses (sarbecoviruses), mosaic nanoparticles presenting receptor-binding domains (RBDs) multiple sarbecoviruses have been developed elicit cross-reactive antibodies that target conserved regions RBD. To better understand vaccination with these antigens, we a computational model humoral nanoparticle spike antigens using combination molecular dynamics, Markov processes, population dynamics simulations....
Abstract There is an urgent need for inexpensive, population-wide surveillance testing COVID-19. We tested newborn dried blood spots (DBS) anti-SARS-COV-2 antibodies all infants born at Yale from March-May 2020, and found that DBS serologies reflect maternal infection rates during the study period. This suggests a role in COVID-19 areas where viral limited.
Abstract To infect, enveloped viruses employ spike protein, spearheaded by its amphipathic fusion peptide (FP), that upon activation extends out from the viral surface to embed into target cellular membrane. Here we report synthesized influenza virus FP are membrane active, generating pores in giant unilamellar vesicles (GUV), and thus potentially explain both virus’ hemolytic activity liposome poration seen cryo-electron tomography. Experimentally, were heterogeneously distributed on GUV at...
Abstract Healthcare workers (HCW) due to occupational exposure patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a population at risk during the current disease-2019 (COVID-19) pandemic. Pre-existing immunity induced by exposition several pathogens, including viruses, can shape susceptibility infections but little is known about presence of cross-reactive memory T cells that have potential recognize SARS-CoV-2. Herein we measured CD4+ cell...