Structure and Dynamics of Confined Water Inside Diphenylalanine Peptide Nanotubes.

Diphenylalanine (FF) peptides exhibit a unique ability to self-assemble into nanotubes with confined water molecules playing pivotal roles in their structure and function. This study investigates the structure and dynamics of diphenylalanine peptide nanotubes (FFPNTs) using all-atom molecular dynamics (MD) and grand canonical Monte Carlo combined with MD (GCMC/MD) simulations with both the CHARMM additive and Drude polarizable force fields. The occupancy and dynamics of confined water molecules were also examined. It was found that less than 2 confined water molecules per FF help stabilize the FFPNTs on the x-y plane. Analyses of the kinetics of confined water molecules revealed distinctive transport behaviors for bound and free water, and their respective diffusion coefficients were compared. Our results validate the importance of polarizable force field models in studying peptide nanotubes and provide insights into our understanding of nanoconfined water.

Binding Energy and Free Energy of Calcium Ion to Calmodulin EF-Hands with the Drude Polarizable Force Field.

Calcium ions are important messenger molecules in cells, which bind calcium-binding proteins to trigger many biochemical processes. We constructed four model systems, each containing one EF-hand loop of calmodulin with one calcium ion bound, and investigated the binding energy and free energy of Ca2+ by the quantum mechanics symmetry-adapted perturbation theory (SAPT) method and the molecular mechanics with the additive CHARMM36m (C36m) and the polarizable Drude force fields (FFs). Our results show that the explicit introduction of polarizability in the Drude not only yields considerably improved agreement with the binding energy calculated from the SAPT method but is also able to capture each component of the binding energies including electrostatic, induction, exchange, and dispersion terms. However, binding free energies computed with the Drude and the C36m FFs both deviated significantly from the experimental measurements. Detailed analysis indicated that one of main reasons might be that the strong interactions between Ca2+ and the side chain nitrogen of Asn/Gln in the Drude FF caused the distorted coordination geometries of calcium. Our work illustrated the importance of polarization in modeling ion-protein interactions and the difficulty in generating accurate and balanced FF models to represent the polarization effects.

The mobility and solvation structure of a hydroxyl radical in a water nanodroplet: a Born-Oppenheimer molecular dynamics study.

Hydroxyl radicals (OH*) play a crucial role in atmospheric chemistry and biological processes. In this study, Born-Oppenheimer molecular dynamics simulations are performed under ambient conditions for a hydroxyl radical in a water nanodroplet containing 191 water molecules. Density functional theory calculations are performed at the BLYP-D3 level with some test calculations at the B3LYP-D3 level. In two 150 ps trajectories, either with OH* initially located in the interior region or at the surface of the water nanodroplet, the OH* radical ends up in the subsurface layer of the nanodroplet, which is different from the "surface preference" predicted from previous empirical force field simulations. The solvation structure of OH* contains fluctuating hydrogen bonds, as well as a two-center three-electron hemibond in some cases. The mobility of OH* is enhanced by hydrogen transfer, which has a free energy barrier of ∼4.6 kcal mol-1. The results presented in this study deepen our understanding of the structure and dynamics of OH* in aqueous solutions, especially around the air-water interface.

AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells.

The current coronavirus disease 2019 (COVID-19) pandemic presents a global public health challenge. The viral pathogen responsible, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), binds to the host receptor ACE2 through its spike (S) glycoprotein, which mediates membrane fusion and viral entry. Although the role of ACE2 as a receptor for SARS-CoV-2 is clear, studies have shown that ACE2 expression is extremely low in various human tissues, especially in the respiratory tract. Thus, other host receptors and/or co-receptors that promote the entry of SARS-CoV-2 into cells of the respiratory system may exist. In this study, we found that the tyrosine-protein kinase receptor UFO (AXL) specifically interacts with the N-terminal domain of SARS-CoV-2 S. Using both a SARS-CoV-2 virus pseudotype and authentic SARS-CoV-2, we found that overexpression of AXL in HEK293T cells promotes SARS-CoV-2 entry as efficiently as overexpression of ACE2, while knocking out AXL significantly reduces SARS-CoV-2 infection in H1299 pulmonary cells and in human primary lung epithelial cells. Soluble human recombinant AXL blocks SARS-CoV-2 infection in cells expressing high levels of AXL. The AXL expression level is well correlated with SARS-CoV-2 S level in bronchoalveolar lavage fluid cells from COVID-19 patients. Taken together, our findings suggest that AXL is a novel candidate receptor for SARS-CoV-2 which may play an important role in promoting viral infection of the human respiratory system and indicate that it is a potential target for future clinical intervention strategies.

Scan and Unlock: A Programmable DNA Molecular Automaton for Cell-Selective Activation of Ligand-Based Signaling.

Selective modulation of ligand-receptor interaction is essential in targeted therapy. In this study, we design an intelligent "scan and unlock" DNA automaton (SUDA) system to equip a native protein-ligand with cell-identity recognition and receptor-mediated signaling in a cell-type-specific manner. Using embedded DNA-based chemical reaction networks (CRNs) on the cell surface, SUDA scans and evaluates molecular profiles of cell-surface proteins via Boolean logic circuits. Therefore, it achieves cell-specific signal modulation by quickly unlocking the protein-ligand in proximity to the target cell-surface to activate its cognate receptor. As a proof of concept, we non-genetically engineered hepatic growth factor (HGF) with distinct logic SUDAs to elicit target cell-specific HGF signaling and wound healing behaviors in multiple heterogeneous cell types. Furthermore, the versatility of the SUDA strategy was shown by engineering tumor necrotic factor-α (TNFα) to induce programmed cell death of target cell subpopulations through cell-specific modulation of TNFR1 signaling.

In†Situ Thermal Atomization To Convert Supported Nickel Nanoparticles into Surface-Bound Nickel Single-Atom Catalysts.

The arrangement of the active sites on the surface of a catalysts can reduce the problem of mass transfer and enhance the atom economy. Herein, supported Ni metal nanoparticles can be transformed to thermal stable Ni single atoms, mostly located on the surface of the support. Assisted by N-doped carbon with abundant defects, this synthetic process not only transform the nanoparticles to single atoms, but also creates numerous pores to facilitate the contact of dissolved CO2 and single Ni sites. The proposed mechanism is that the Ni nanoparticles could break surface C-C bonds drill into the carbon matrix, leaving pores on the surface. When Ni nanoparticles are exposed to N-doped carbon, the strong coordination splits Ni atoms from Ni NPs. The Ni atoms are stabilized within the surface of carbon substrate. The continuous loss of atomic Ni species from the NPs would finally result in atomization of Ni NPs. CO2 electroreduction testing shows that the surface enriched with Ni single atoms delivers better performance than supported Ni NPs and other similar catalysts.

Atomistic Simulations of Graphene Growth: From Kinetics to Mechanism.

Epitaxial growth is a promising strategy to produce high-quality graphene samples. At the same time, this method has great flexibility for industrial scale-up. To optimize growth protocols, it is essential to understand the underlying growth mechanisms. This is, however, very challenging, as the growth process is complicated and involves many elementary steps. Experimentally, atomic-scale in situ characterization methods are generally not feasible at the high temperature of graphene growth. Therefore, kinetics is the main experimental information to study growth mechanisms. Theoretically, first-principles calculations routinely provide atomic structures and energetics but have a stringent limit on the accessible spatial and time scales. Such gap between experiment and theory can be bridged by atomistic simulations using first-principles atomic details as input and providing the overall growth kinetics, which can be directly compared with experiment, as output. Typically, system-specific approximations should be applied to make such simulations computationally feasible. By feeding kinetic Monte Carlo (kMC) simulations with first-principles parameters, we can directly simulate the graphene growth process and thus understand the growth mechanisms. Our simulations suggest that the carbon dimer is the dominant feeding species in the epitaxial growth of graphene on both Cu(111) and Cu(100) surfaces, which enables us to understand why the reaction is diffusion limited on Cu(111) but attachment limited on Cu(100). When hydrogen is explicitly considered in the simulation, the central role hydrogen plays in graphene growth is revealed, which solves the long-standing puzzle into why H2 should be fed in the chemical vapor deposition of graphene. The simulation results can be directly compared with the experimental kinetic data, if available. Our kMC simulations reproduce the experimentally observed quintic-like behavior of graphene growth on Ir(111). By checking the simulation results, we find that such nonlinearity is caused by lattice mismatch, and the induced growth front inhomogeneity can be universally used to predict growth behaviors in other heteroepitaxial systems. Notably, although experimental kinetics usually gives useful insight into atomic mechanisms, it can sometimes be misleading. Such pitfalls can be avoided via atomistic simulations, as demonstrated in our study of the graphene etching process. Growth protocols can be designed theoretically with computational kinetic and mechanistic information. By contrasting the different activation energies involved in an atom-exchange-based carbon penetration process for monolayer and bilayer graphene, we propose a three-step strategy to grow high-quality bilayer graphene. Based on first-principles parameters, a kinetic pathway toward the high-density, ordered N doping of epitaxial graphene on Cu(111) using a C5NCl5 precursor is also identified. These studies demonstrate that atomistic simulations can unambiguously produce or reproduce the kinetic information on graphene growth, which is pivotal to understanding the growth mechanism and designing better growth protocols. A similar strategy can be used in growth mechanism studies of other two-dimensional atomic crystals.

The Nanoparticle Size Effect in Graphene Cutting: A "Pac-Man" Mechanism.

Metal-nanoparticle-catalyzed cutting is a promising way to produce graphene nanostructures with smooth and well-aligned edges. Using a multiscale simulation approach, we unambiguously identified a "Pac-Man" cutting mechanism, characterized by the metal nanoparticle "biting off" edge carbon atoms through a synergetic effect of multiple metal atoms. By comparing the reaction rates at different types of edge sites, we found that etching of an entire edge carbon row could be triggered by a single zigzag-site etching event, which explains the puzzling linear dependence of the overall carbon-atom etching rate on the nanoparticle surface area observed experimentally. With incorporation of the nanoparticle size effect, the mechanisms revealed herein open a new avenue to improve controllability in graphene cutting.