Starting from late 2019, the coronavirus disease 2019 (COVID-19) has emerged as a once-in-a-century pandemic with deadly consequences, which urgently calls for new treatments, cures, and supporting ...apparatuses. Recently, because of its positive results in clinical trials, remdesivir was approved by the Food and Drug Administration to treat COVID-19 through Emergency Use Authorization. Here, we used molecular dynamics simulations and free energy perturbation methods to study the inhibition mechanism of remdesivir to its target SARS-CoV-2 virus RNA-dependent RNA polymerase (RdRp). We first constructed the homology model of this polymerase based on a previously available structure of SARS-CoV NSP12 RdRp (with a sequence identity of 95.8%). We then built a putative preinsertion binding structure by aligning the remdesivir + RdRp complex to the ATP bound poliovirus RdRp without the RNA template. The putative binding structure was further optimized with molecular dynamics simulations. The resulting stable preinsertion state of remdesivir appeared to form hydrogen bonds with the RNA template when aligned with the newly solved cryo-EM structure of SARS-CoV-2 RdRp. The relative binding free energy between remdesivir and ATP was calculated to be −2.80 ± 0.84 kcal/mol, where remdesivir bound much stronger to SARS-CoV-2 RdRp than the natural substrate ATP. The ∼100-fold improvement in the K d from remdesivir over ATP indicates an effective replacement of ATP in blocking of the RdRp preinsertion site. Key residues D618, S549, and R555 are found to be the contributors to the binding affinity of remdesivir. These findings suggest that remdesivir can potentially act as a SARS-CoV-2 RNA-chain terminator, effectively stopping its RNA replication, with key residues also identified for future lead optimization and/or drug resistance studies.
Single-stranded DNA (ssDNA) molecules in solution typically form coiled structures, therefore stretching ssDNA is extremely crucial before applying any nanotechnology for ssDNA analysis. Recent ...advances in material fabrication enable the deployment of nanochannels to manipulate, stretch, sort and map double-stranded DNA (dsDNA) molecules, however nanochannels fail to stretch ssDNA molecules due to the ultra-short persistence length and the potential nonspecific-interaction-induced clogging. Given the significance of ssDNA stretching in genome analysis, here we report an ssDNA stretching platform: two dimensional in-plane heterostructure comprising graphene and hexagonal boron nitride (h-BN), and show that ssDNA can be stretched on a h-BN nanostripe sandwiched between two adjacent graphene domains ("nanochannel"). We further show that with a biasing voltage the stretched ssDNA can be electrophoretically transported along the "nanochannel", allowing easy controls/manipulations. When being conveniently integrated with existing atomic resolution sensors, the heterostructure platform paves the way for sequencing DNA on a planar surface.
CD8
T cell-dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific ...HLA-I genotype influences response to anti-programmed cell death protein 1 or anti-cytotoxic T lymphocyte-associated protein 4 is currently unknown. We determined the HLA-I genotype of 1535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci ("A," "B," and "C") improved overall survival after ICB compared with patients who were homozygous for at least one HLA locus. In two independent melanoma cohorts, patients with the HLA-B44 supertype had extended survival, whereas the HLA-B62 supertype (including HLA-B*15:01) or somatic loss of heterozygosity at HLA-I was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed different elements that may impair CD8
T cell recognition of neoantigens. Our results have important implications for predicting response to ICB and for the design of neoantigen-based therapeutic vaccines.
The deteriorating state of global fresh water resources represents one of the most serious challenges that scientists and policymakers currently face. Desalination technologies, which are designed to ...extract potable water from the planet’s bountiful stores of seawater, could serve to alleviate much of the stress that presently plagues fresh water supplies. In recent decades, desalination methods have improved via water-filtering architectures based on nanoporous graphene filters and artificial membranes integrated with biological water channels. Here, we report the auspicious performance (in simulations) of an alternative nanoporous desalination filter constructed from a MoS2 nanosheet. In striking contrast to graphene-based filters, we find that the “open” and “closed” states of the MoS2 filter can be regulated by the introduction of mechanical strain, yielding a highly tunable nanopore interface. By applying lateral strain to the MoS2 filter in our simulations, we see that the transition point between “open” and “closed” states occurs under tension that induces about 6% cross-sectional expansion in the membrane (6% strain); the open state of the MoS2 filter demonstrates high water transparency and a strong salt filtering capability even under 12% strain. Our results thus demonstrate the promise of a controllable nanoporous MoS2 desalination filter, wherein the morphology and size of the central nanopore can be precisely regulated by tensile strain. These findings support the design and proliferation of tunable nanodevices for filtration and other applications.
Noble metal-based nanomaterials have shown promise as potential enzyme mimetics, but the facet effect and underlying molecular mechanisms are largely unknown. Herein, with a combined experimental and ...theoretical approach, we unveil that palladium (Pd) nanocrystals exhibit facet-dependent oxidase and peroxidase-like activities that endow them with excellent antibacterial properties via generation of reactive oxygen species. The antibacterial efficiency of Pd nanocrystals against Gram-positive bacteria is consistent with the extent of their enzyme-like activity, that is {100}-faceted Pd cubes with higher activities kill bacteria more effectively than {111}-faceted Pd octahedrons. Surprisingly, a reverse trend of antibacterial activity is observed against Gram-negative bacteria, with Pd octahedrons displaying stronger penetration into bacterial membranes than Pd nanocubes, thereby exerting higher antibacterial activity than the latter. Our findings provide a deeper understanding of facet-dependent enzyme-like activities and might advance the development of noble metal-based nanomaterials with both enhanced and targeted antibacterial activities.
Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure. This dire situation calls for research into the origin and pathological ...manifestations of amyloidosis to stimulate continued development of new therapeutics. In basic science and engineering, the cross-β architecture has been a constant thread underlying the structural characteristics of pathological and functional amyloids, and realizing that amyloid structures can be both pathological and functional in nature has fuelled innovations in artificial amyloids, whose use today ranges from water purification to 3D printing. At the conclusion of a half century since Eanes and Glenner's seminal study of amyloids in humans, this review commemorates the occasion by documenting the major milestones in amyloid research to date, from the perspectives of structural biology, biophysics, medicine, microbiology, engineering and nanotechnology. We also discuss new challenges and opportunities to drive this interdisciplinary field moving forward.
Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure.
The adsorption of protein villin headpiece (HP35) onto a graphene has been investigated using large scale molecular dynamics simulations, and the results are compared with similar adsorptions onto a ...single-wall carbon nanotube and a fullerene, C60. It is found that HP35 loses most of its native secondary and tertiary structures after the adsorption onto graphene. The π–π stacking interactions between the graphene and HP35’s aromatic residues play a key role in this adsorption. The graphene’s softness also helps the binding by adapting its own shape to fit better with aromatic residues in forming stronger π–π stacking interactions. Interestingly, the mechanism of HP35 adsorption onto the other two graphitic nanomaterials is found to be somewhat different, in which the π–π stacking interactions play a lesser role than the dispersion interactions between the nanomaterial and HP35’s aliphatic side chains. These findings indicate that in addition to the chemical composition, the shape of the nanoparticle is also an important factor in determining its interaction with proteins: the contacting surface curvature can lead to different adsorption mechanisms.
Transcription activator-like effectors are sequence-specific DNA-binding proteins that harbour modular, repetitive DNA-binding domains. Transcription activator-like effectors have enabled the ...creation of customizable designer transcriptional factors and sequence-specific nucleases for genome engineering. Here we report two improvements of the transcription activator-like effector toolbox for achieving efficient activation and repression of endogenous gene expression in mammalian cells. We show that the naturally occurring repeat-variable diresidue Asn-His (NH) has high biological activity and specificity for guanine, a highly prevalent base in mammalian genomes. We also report an effective transcription activator-like effector transcriptional repressor architecture for targeted inhibition of transcription in mammalian cells. These findings will improve the precision and effectiveness of genome engineering that can be achieved using transcription activator-like effectors.
Metal-organic frameworks (MOFs) based on zirconium phosphonates exhibit superior chemical stability suitable for applications under harsh conditions. These compounds mostly exist as poorly ...crystallized precipitates, and precise structural information has therefore remained elusive. Furthermore, a zero-dimensional zirconium phosphonate cluster acting as secondary building unit has been lacking, leading to poor designability in this system. Herein, we overcome these challenges and obtain single crystals of three zirconium phosphonates that are suitable for structural analysis. These compounds are built by previously unknown isolated zirconium phosphonate clusters and exhibit combined high porosity and ultrastability even in fuming acids. SZ-2 possesses the largest void volume recorded in zirconium phosphonates and SZ-3 represents the most porous crystalline zirconium phosphonate and the only porous MOF material reported to survive in aqua regia. SZ-2 and SZ-3 can effectively remove uranyl ions from aqueous solutions over a wide pH range, and we have elucidated the removal mechanism.
Many environmental pollutants inherently exist in their anionic forms and are therefore highly mobile in natural water systems. Cationic framework materials that can capture those pollutants are ...highly desirable but scarcely reported. Here we present a mesoporous cationic thorium-based MOF (SCU-8) containing channels with a large inner diameter of 2.2 nm and possessing a high surface area of 1360 m
g
. The anion-exchange properties of SCU-8 were explored with many anions including small oxo anions like ReO
and Cr
O
as well as anionic organic dyes like methyl blue and the persistent organic pollutant, perfluorooctane sulfonate (PFOS). Both fast uptake kinetics and great sorption selectivity toward PFOS are observed. The underlying sorption mechanism was probed using quantum mechanical and molecular dynamics simulations. These computational results reveal that PFOS anions are immobilized in SCU-8 by driving forces including electrostatic interactions, hydrogen bonds, hydrophobic interactions, and van der Waals interactions at different adsorption stages.
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