Modeling of ACE2 and antibodies bound to SARS-CoV-2 provides insights into infectivity and immune evasion.

Given the COVID-19 pandemic, there is interest in understanding ligand-receptor features and targeted antibody-binding attributes against emerging SARS-CoV-2 variants. Here, we developed a large-scale structure-based pipeline for analysis of protein-protein interactions regulating SARS-CoV-2 immune evasion. First, we generated computed structural models of the Spike protein of 3 SARS-CoV-2 variants (B.1.1.529, BA.2.12.1, and BA.5) bound either to a native receptor (ACE2) or to a large panel of targeted ligands (n = 282), which included neutralizing or therapeutic monoclonal antibodies. Moreover, by using the Barnes classification, we noted an overall loss of interfacial interactions (with gain of new interactions in certain cases) at the receptor-binding domain (RBD) mediated by substituted residues for neutralizing complexes in classes 1 and 2, whereas less destabilization was observed for classes 3 and 4. Finally, an experimental validation of predicted weakened therapeutic antibody binding was performed in a cell-based assay. Compared with the original Omicron variant (B.1.1.529), derivative variants featured progressive destabilization of antibody-RBD interfaces mediated by a larger set of substituted residues, thereby providing a molecular basis for immune evasion. This approach and findings provide a framework for rapidly and efficiently generating structural models for SARS-CoV-2 variants bound to ligands of mechanistic and therapeutic value.

Structural models of SARS-CoV-2 Omicron variant in complex with ACE2 receptor or antibodies suggest altered binding interfaces.

There is enormous ongoing interest in characterizing the binding properties of the SARS-CoV-2 Omicron Variant of Concern (VOC) (B.1.1.529), which continues to spread towards potential dominance worldwide. To aid these studies, based on the wealth of available structural information about several SARS-CoV-2 variants in the Protein Data Bank (PDB) and a modeling pipeline we have previously developed for tracking the ongoing global evolution of SARS-CoV-2 proteins, we provide a set of computed structural models (henceforth models) of the Omicron VOC receptor-binding domain (omRBD) bound to its corresponding receptor Angiotensin-Converting Enzyme (ACE2) and a variety of therapeutic entities, including neutralizing and therapeutic antibodies targeting previously-detected viral strains. We generated bound omRBD models using both experimentally-determined structures in the PDB as well as machine learningbased structure predictions as starting points. Examination of ACE2-bound omRBD models reveals an interdigitated multi-residue interaction network formed by omRBD-specific substituted residues (R493, S496, Y501, R498) and ACE2 residues at the interface, which was not present in the original Wuhan-Hu-1 RBD-ACE2 complex. Emergence of this interaction network suggests optimization of a key region of the binding interface, and positive cooperativity among various sites of residue substitutions in omRBD mediating ACE2 binding. Examination of neutralizing antibody complexes for Barnes Class 1 and Class 2 antibodies modeled with omRBD highlights an overall loss of interfacial interactions (with gain of new interactions in rare cases) mediated by substituted residues. Many of these substitutions have previously been found to independently dampen or even ablate antibody binding, and perhaps mediate antibody-mediated neutralization escape ( e.g ., K417N). We observe little compensation of corresponding interaction loss at interfaces when potential escape substitutions occur in combination. A few selected antibodies ( e.g ., Barnes Class 3 S309), however, feature largely unaltered or modestly affected protein-protein interfaces. While we stress that only qualitative insights can be obtained directly from our models at this time, we anticipate that they can provide starting points for more detailed and quantitative computational characterization, and, if needed, redesign of monoclonal antibodies for targeting the Omicron VOC Spike protein. In the broader context, the computational pipeline we developed provides a framework for rapidly and efficiently generating retrospective and prospective models for other novel variants of SARS-CoV-2 bound to entities of virological and therapeutic interest, in the setting of a global pandemic.

OSG-GEM: Gene Expression Matrix Construction Using the Open Science Grid.

High-throughput DNA sequencing technology has revolutionized the study of gene expression while introducing significant computational challenges for biologists. These computational challenges include access to sufficient computer hardware and functional data processing workflows. Both these challenges are addressed with our scalable, open-source Pegasus workflow for processing high-throughput DNA sequence datasets into a gene expression matrix (GEM) using computational resources available to U.S.-based researchers on the Open Science Grid (OSG). We describe the usage of the workflow (OSG-GEM), discuss workflow design, inspect performance data, and assess accuracy in mapping paired-end sequencing reads to a reference genome. A target OSG-GEM user is proficient with the Linux command line and possesses basic bioinformatics experience. The user may run this workflow directly on the OSG or adapt it to novel computing environments.

Ambient temperature operated acetaldehyde vapour detection of spray deposited cobalt doped zinc oxide thin film.

Undoped and Co-doped ZnO thin films were prepared by a home built spray pyrolysis method. X-ray diffraction results indicate that both undoped and Co-doped ZnO have a polycrystalline nature and a preferential orientation peak in the (002) plane. From a field-emission scanning electron micrographs of annealed films, a uniform distribution of nanoparticles along with nanorods was observed. UV-Visible measurement indicated that all the films are transparent in the visible region. The electrical resistance was also reported. The acetaldehyde sensing behaviour of the prepared undoped and Co-doped ZnO thin films was studied using the chemi-resistive method at ambient temperature (∼30 °C). In the presence of 10 ppm of acetaldehyde vapour, the Co-doped ZnO thin films showed good sensing response of 74% with fast response and recovery time of 3 s and 110 s respectively.

Electrostatics, structure prediction, and the energy landscapes for protein folding and binding.

While being long in range and therefore weakly specific, electrostatic interactions are able to modulate the stability and folding landscapes of some proteins. The relevance of electrostatic forces for steering the docking of proteins to each other is widely acknowledged, however, the role of electrostatics in establishing specifically funneled landscapes and their relevance for protein structure prediction are still not clear. By introducing Debye-Hückel potentials that mimic long-range electrostatic forces into the Associative memory, Water mediated, Structure, and Energy Model (AWSEM), a transferable protein model capable of predicting tertiary structures, we assess the effects of electrostatics on the landscapes of thirteen monomeric proteins and four dimers. For the monomers, we find that adding electrostatic interactions does not improve structure prediction. Simulations of ribosomal protein S6 show, however, that folding stability depends monotonically on electrostatic strength. The trend in predicted melting temperatures of the S6 variants agrees with experimental observations. Electrostatic effects can play a range of roles in binding. The binding of the protein complex KIX-pKID is largely assisted by electrostatic interactions, which provide direct charge-charge stabilization of the native state and contribute to the funneling of the binding landscape. In contrast, for several other proteins, including the DNA-binding protein FIS, electrostatics causes frustration in the DNA-binding region, which favors its binding with DNA but not with its protein partner. This study highlights the importance of long-range electrostatics in functional responses to problems where proteins interact with their charged partners, such as DNA, RNA, as well as membranes.

Unraveling the Mechanism of Photoinduced Charge Transfer in Carotenoid-Porphyrin-C60 Molecular Triad.

Photoinduced charge transfer (CT) plays a central role in biologically significant systems and in applications that harvest solar energy. We investigate the relationship of CT kinetics and conformation in a molecular triad. The triad, consisting of carotenoid, porphyrin, and fullerene is structurally flexible and able to acquire significantly varied conformations under ambient conditions. With an integrated approach of quantum calculations and molecular dynamics simulations, we compute the rate of CT at two distinctive conformations. The linearly extended conformation, in which the donor (carotenoid) and the acceptor (fullerene) are separated by nearly 50 Å, enables charge separation through a sequential CT process. A representative bent conformation that is entropically dominant, however, attenuates the CT, although the donor and the acceptor are spatially closer. Our computed rate of CT at the linear conformation is in good agreement with measured values. Our work provides unique fundamental understanding of the photoinduced CT process in the molecular triad.

Two-Electron Transfer Pathways.

The frontiers of electron-transfer chemistry demand that we develop theoretical frameworks to describe the delivery of multiple electrons, atoms, and ions in molecular systems. When electrons move over long distances through high barriers, where the probability for thermal population of oxidized or reduced bridge-localized states is very small, the electrons will tunnel from the donor (D) to acceptor (A), facilitated by bridge-mediated superexchange interactions. If the stable donor and acceptor redox states on D and A differ by two electrons, it is possible that the electrons will propagate coherently from D to A. While structure-function relations for single-electron superexchange in molecules are well established, strategies to manipulate the coherent flow of multiple electrons are largely unknown. In contrast to one-electron superexchange, two-electron superexchange involves both one- and two-electron virtual intermediate states, the number of virtual intermediates increases very rapidly with system size, and multiple classes of pathways interfere with one another. In the study described here, we developed simple superexchange models for two-electron transfer. We explored how the bridge structure and energetics influence multielectron superexchange, and we compared two-electron superexchange interactions to single-electron superexchange. Multielectron superexchange introduces interference between singly and doubly oxidized (or reduced) bridge virtual states, so that even simple linear donor-bridge-acceptor systems have pathway topologies that resemble those seen for one-electron superexchange through bridges with multiple parallel pathways. The simple model systems studied here exhibit a richness that is amenable to experimental exploration by manipulating the multiple pathways, pathway crosstalk, and changes in the number of donor and acceptor species. The features that emerge from these studies may assist in developing new strategies to deliver multiple electrons in condensed-phase redox systems, including multiple-electron redox species, multimetallic/multielectron redox catalysts, and multiexciton excited states.

Dye-sensitized solar cell based on spray deposited ZnO thin film: performance analysis through DFT approach.

A dye-sensitized solar cell based on a spray deposited zinc oxide (ZnO) photoanode with Evans blue as a sensitizer was fabricated. Structural analysis confirms the hexagonal wurtzite phase of the ZnO photoanode with c-axis orientation. Surface morphology of the ZnO photoanode shows uniform distribution of spherically-shaped grains, ranging from 18 nm to 25 nm. The power conversion efficiency of the device was measured as 0.1%. Density functional theory was adopted to study the observed photovoltaic performance of the fabricated device. The analysis of the electronic properties of Evans blue dye showed that it has a pronounced effect on the observed device performance.

Multiscale simulation of the ground and photo-induced charge-separated states of a molecular triad in polar organic solvent: exploring the conformations, fluctuations, and free energy landscapes.

The approach of a multiscale simulation that combines quantum chemical calculations, classical molecular dynamics simulations, and statistical physics to integrate the information of the electronic states of a conformationally complex molecule into its structural distribution over an ensemble was performed to understand the influence of a polar organic solvent on the structural stability of carotene-porphyrin-fullerene molecular triad in both the ground and the photoinduced charge-separated excited states. The excited states of the triad were computed with the ab initio quantum chemical calculations using the algebraic diagrammatic construction through the second order correction (ADC(2)) method and the time-dependent density functional theory (TDDFT). The replica exchange molecular dynamics was used for the enhanced sampling of the ensemble in order to explore the phase space of the ground state and the photoinduced charge-separated excited state of triad in explicit tetrahydrofuran (THF) solvent. An importance sampling was strategically employed to bridge the gap between the two computational methods that aim to explore distinct realms of dynamics. We analyzed the free energy landscape, the structural fluctuations, the solvent arrangements, the static dielectric constant, and the interactions between the triad and the solvent molecules. The analysis of the free energy landscape of the triad indicates that the charge-separated excited state of the triad is thermodynamically stable in a linearly extended geometry, while the ground-state triad explores several extended and bent conformations that are populated in the local free energy minima separated by low free energy barriers at an order of thermal fluctuation (k(B)T). The stabilization of a linearly extended structure of the charge-separated excited state triad is predominantly due to the solvation interactions (van der Waals and electrostatic interactions) between the triad and the THF molecules as well as the interactions within the THF molecules. Differences in the charge distribution on a molecular triad induce slight changes in the dielectric property of THF near the triad. Our study suggests that by measuring the differences in a dielectric response of solvent near the triad, it is possible to provide insight into the population of the charge-separated electronic state of the triad relative to that of the ground state.

Exploring chemical space with discrete, gradient, and hybrid optimization methods.

Discrete, gradient, and hybrid optimization methods are applied to the challenge of discovering molecules with optimized properties. The cost and performance of the approaches were studied using a tight-binding model to maximize the static first electronic hyperpolarizability of molecules. Our analysis shows that discrete branch and bound methods provide robust strategies for inverse chemical design involving diverse chemical structures. Based on the linear combination of atomic potentials, a hybrid discrete-gradient optimization strategy significantly improves the performance of the gradient methods. The hybrid method performs better than dead-end elimination and competes with branch and bound and genetic algorithms. The branch and bound methods for these model Hamiltonians are more cost effective than genetic algorithms for moderate-sized molecular optimization.

Circular dichroism spectra of DNA hairpins studied by the green function method.

The circular dichroism (CD) spectrum of a large biological molecule represented as an array of interacting chromophores is investigated. The configuration-averaged Green function formalism is developed to describe the CD and absorption spectra. The perturbation theory expansion is derived for absorption and CD spectra in the case of strong interaction of chromophores with their environment (solvent and/or internal dynamics) compared to their interaction with each other. We apply this formalism to study CD spectra of DNA hairpins.