Insights from 20 years of the Molecule of the Month.

For 20 years, Molecule of the Month articles have highlighted the functional stories of 3D structures found in the Protein Data Bank (PDB). The PDB is the primary archive of atomic structures of biological molecules, currently providing open access to more than 150,000 structures studied by researchers around the world. The wealth of knowledge embodied in this resource is remarkable, with structures that allow exploration of nearly any biomolecular topic, including the basic science of genetic mechanisms, mechanisms of photosynthesis and bioenergetics, and central biomedical topics like cancer therapy and the fight against infectious disease.

A Water Molecule Residing in the Fe···Cu Dinuclear Center of the Resting Oxidized as-Isolated Cytochrome Oxidase: A Density Functional Study.

Although the dinuclear center (DNC) of the resting oxidized "as-isolated" cytochrome oxidase (CO) is not a catalytically active state, its detailed structure, especially the nature of the bridging species between the Fe and Cu metal sites, is still both relevant and unsolved. Recent crystallographic work has shown an extended electron density for a peroxide type dioxygen species (O1-O2) bridging the Fe and Cu centers. In this paper, our density functional theory (DFT) calculations show that the observed peroxide type electron density between the two metal centers is most likely a mistaken analysis due to overlap of the electron density of a water molecule located at different positions between apparent O1 and O2 sites in DNCs of different CO molecules with almost the same energy.

Parallel Implementation of Density Functional Theory Methods in the Quantum Interaction Computational Kernel Program.

We present the details of a graphics processing unit (GPU) capable exchange correlation (XC) scheme integrated into the open source QUantum Interaction Computational Kernel (QUICK) program. Our implementation features an octree based numerical grid point partitioning scheme, GPU enabled grid pruning and basis and primitive function prescreening, and fully GPU capable XC energy and gradient algorithms. Benchmarking against the CPU version demonstrated that the GPU implementation is capable of delivering an impressive performance while retaining excellent accuracy.

NWChem: Past, present, and future.

Specialized computational chemistry packages have permanently reshaped the landscape of chemical and materials science by providing tools to support and guide experimental efforts and for the prediction of atomistic and electronic properties. In this regard, electronic structure packages have played a special role by using first-principle-driven methodologies to model complex chemical and materials processes. Over the past few decades, the rapid development of computing technologies and the tremendous increase in computational power have offered a unique chance to study complex transformations using sophisticated and predictive many-body techniques that describe correlated behavior of electrons in molecular and condensed phase systems at different levels of theory.

The open EEGLAB portal Interface: High-Performance computing with EEGLAB.

EEGLAB signal processing environment is currently the leading open-source software for processing electroencephalographic (EEG) data. The Neuroscience Gateway (NSG, nsgportal.org) is a web and API-based portal allowing users to easily run a variety of neuroscience-related software on high-performance computing (HPC) resources in the U.

MicrographCleaner: A python package for cryo-EM micrograph cleaning using deep learning.

Cryo-EM Single Particle Analysis workflows require tens of thousands of high-quality particle projections to unveil the three-dimensional structure of macromolecules. Conventional methods for automatic particle picking tend to suffer from high false-positive rates, hampering the reconstruction process. One common cause of this problem is the presence of carbon and different types of high-contrast contaminations.

Nature of Alkali Ion-Water Interactions: Insights from Many-Body Representations and Density Functional Theory. II.

Interaction energies of alkali ion-water dimers, M(HO), and trimers, M(HO), with M = Li, Na, K, Rb, and Cs, are investigated using various many-body potential energy functions and exchange-correlation functionals selected across the hierarchy of density functional theory approximations. Analysis of interaction energy decompositions indicates that close-range interactions such as Pauli repulsion, charge transfer, and charge penetration must be captured in order to reproduce accurate interaction energies. In particular, it is found that simple classical polarizable models must be supplemented with dedicated terms which account for these close-range interactions in order to achieve chemical accuracy.

Examining LI-RADS recommendations: should observation size only be measured on non-arterial phases?

Objective: To investigate if size measurements of liver observations is more variable in the arterial phase as suggested by LI-RADS and assess potential higher instability in categorization in this particular phase. Secondarily, to assess inter- and intra-reader agreement for size across phases.

Materials And Methods: Patients with liver cirrhosis who underwent multi-arterial phase MRI between 2017 and 2018 were retrospectively selected.

Computer simulations explain mutation-induced effects on the DNA editing by adenine base editors.

Adenine base editors, which were developed by engineering a transfer RNA adenosine deaminase enzyme (TadA) into a DNA editing enzyme (TadA*), enable precise modification of A:T to G⋮C base pairs. Here, we use molecular dynamics simulations to uncover the structural and functional roles played by the initial mutations in the onset of the DNA editing activity by TadA*. Atomistic insights reveal that early mutations lead to intricate conformational changes in the structure of TadA*.

Low-order many-body interactions determine the local structure of liquid water.

Despite its apparent simplicity, water displays unique behavior across the phase diagram which is strictly related to the ability of the water molecules to form dense, yet dynamic, hydrogen-bond networks that continually fluctuate in time and space. The competition between different local hydrogen-bonding environments has been hypothesized as a possible origin of the anomalous properties of liquid water. Through a systematic application of the many-body expansion of the total energy, we demonstrate that the local structure of liquid water at room temperature is determined by a delicate balance between two-body and three-body energies, which is further modulated by higher-order many-body effects.

Data-Driven Many-Body Models for Molecular Fluids: CO/HO Mixtures as a Case Study.

In this study, we extend the scope of the many-body TTM-nrg and MB-nrg potential energy functions (PEFs), originally introduced for halide ion-water and alkali-metal ion-water interactions, to the modeling of carbon dioxide (CO) and water (HO) mixtures as prototypical examples of molecular fluids. Both TTM-nrg and MB-nrg PEFs are derived entirely from electronic structure data obtained at the coupled cluster level of theory and are, by construction, compatible with MB-pol, a many-body PEF that has been shown to accurately reproduce the properties of water. Although both TTM-nrg and MB-nrg PEFs adopt the same functional forms for describing permanent electrostatics, polarization, and dispersion, they differ in the representation of short-range contributions, with the TTM-nrg PEFs relying on conventional Born-Mayer expressions and the MB-nrg PEFs employing multidimensional permutationally invariant polynomials.

Impact of the Protein Data Bank on antineoplastic approvals.

Open access to 3D structure information from the Protein Data Bank (PDB) facilitated discovery and development of >90% of the 79 new antineoplastic agents (54 small molecules, 25 biologics) with known molecular targets approved by the FDA 2010-2018. Analyses of PDB holdings, the scientific literature and related documents for each drug-target combination revealed that the impact of public-domain 3D structure data was broad and substantial, ranging from understanding target biology (∼95% of all targets) to identifying a given target as probably druggable (∼95% of all targets) to structure-guided lead optimization (>70% of all small-molecule drugs). In addition to aggregate impact assessments, illustrative case studies are presented for three protein kinase inhibitors, an allosteric enzyme inhibitor and seven advanced-stage melanoma therapeutics.

LI-RADS ancillary feature prediction of longitudinal category changes in LR-3 observations: an exploratory study.

Purpose: To determine whether LI-RADS ancillary features predict longitudinal LR-3 observation category changes.

Materials And Methods: This exploratory, retrospective, single-center study with an independent reading center included patients who underwent two or more multiphase CT or MRI examinations for hepatocellular carcinoma assessment between 2011 and 2015. Three readers independently evaluated each observation using CT/MRI LI-RADS v2017, and observations categorized LR-3 using major features only were included in the analysis.

Insights from Adopting a Data Commons Approach for Large-scale Observational Cohort Studies: The California Teachers Study.

Background: Large-scale cancer epidemiology cohorts (CEC) have successfully collected, analyzed, and shared patient-reported data for years. CECs increasingly need to make their data more findable, accessible, interoperable, and reusable, or FAIR. How CECs should approach this transformation is unclear.

Influence of Arctic sea-ice variability on Pacific trade winds.

A conceptual model connecting seasonal loss of Arctic sea ice to midlatitude extreme weather events is applied to the 21st-century intensification of Central Pacific trade winds, emergence of Central Pacific El Nino events, and weakening of the North Pacific Aleutian Low Circulation. According to the model, Arctic Ocean warming following the summer sea-ice melt drives vertical convection that perturbs the upper troposphere. Static stability calculations show that upward convection occurs in annual 40- to 45-d episodes over the seasonally ice-free areas of the Beaufort-to-Kara Sea arc.

D3R grand challenge 4: blind prediction of protein-ligand poses, affinity rankings, and relative binding free energies.

The Drug Design Data Resource (D3R) aims to identify best practice methods for computer aided drug design through blinded ligand pose prediction and affinity challenges. Herein, we report on the results of Grand Challenge 4 (GC4). GC4 focused on proteins beta secretase 1 and Cathepsin S, and was run in an analogous manner to prior challenges.

Monitoring and mitigation of toxic heavy metals and arsenic accumulation in food crops: A case study of an urban community garden.

Urban community gardens have increased in prevalence as a means to generate fresh fruits and vegetables, including in areas lacking access to healthy food options. However, urban soils may have high levels of toxic heavy metals, including lead and cadmium and the metalloid arsenic, which can lead to severe health risks. In this study, fruit and vegetable samples grown at an urban community garden in southeastern San Diego, the Ocean View Growing Grounds, were sampled repeatedly over a four-year time period in order to measure potential contamination of toxic heavy metals and metalloids and to develop solutions for this problem.

Effect of cortical bone micro-structure in fragility fracture patients on lamellar stress.

This work investigates how changes in cortical bone microstructure alter the risk of fragility fractures. The secondary osteons of non-osteoporotic (by DXA) women with fragility fractures have reduced lamellar width and greater areas of birefringent brightness in transverse sections, a pathological condition. We used hierarchical finite element (FE) models of the proximal femur of two women aged 67 and 88 (younger and older) during one-legged stance.

Phylogenomics of 10,575 genomes reveals evolutionary proximity between domains Bacteria and Archaea.

Rapid growth of genome data provides opportunities for updating microbial evolutionary relationships, but this is challenged by the discordant evolution of individual genes. Here we build a reference phylogeny of 10,575 evenly-sampled bacterial and archaeal genomes, based on a comprehensive set of 381 markers, using multiple strategies. Our trees indicate remarkably closer evolutionary proximity between Archaea and Bacteria than previous estimates that were limited to fewer "core" genes, such as the ribosomal proteins.

X-ray Crystallographic and Molecular Dynamic Analyses of Drosophila melanogaster Embryonic Muscle Myosin Define Domains Responsible for Isoform-Specific Properties.

Drosophila melanogaster is a powerful system for characterizing alternative myosin isoforms and modeling muscle diseases, but high-resolution structures of fruit fly contractile proteins have not been determined. Here we report the first x-ray crystal structure of an insect myosin: the D melanogaster skeletal muscle myosin II embryonic isoform (EMB). Using our system for recombinant expression of myosin heavy chain (MHC) proteins in whole transgenic flies, we prepared and crystallized stable proteolytic S1-like fragments containing the entire EMB motor domain bound to an essential light chain.

Accuracy of common proton density fat fraction thresholds for magnitude- and complex-based chemical shift-encoded MRI for assessing hepatic steatosis in patients with obesity.

Purpose: MRI proton density fat fraction (PDFF) can be calculated using magnitude (MRI-M) or complex (MRI-C) MRI data. The purpose of this study was to identify, assess, and compare the accuracy of common PDFF thresholds for MRI-M and MRI-C for assessing hepatic steatosis in patients with obesity, using histology as reference.

Methods: This two-center prospective study included patients undergoing MRI-C- and MRI-M-PDFF estimations within 3 days before weight loss surgery.

Federating Structural Models and Data: Outcomes from A Workshop on Archiving Integrative Structures.

Structures of biomolecular systems are increasingly computed by integrative modeling. In this approach, a structural model is constructed by combining information from multiple sources, including varied experimental methods and prior models. In 2019, a Workshop was held as a Biophysical Society Satellite Meeting to assess progress and discuss further requirements for archiving integrative structures.

Gadoxetate-enhanced Abbreviated MRI for Hepatocellular Carcinoma Surveillance: Preliminary Experience.

Purpose: To describe a single-center preliminary experience with gadoxetate disodium-enhanced abbreviated MRI for hepatocellular carcinoma (HCC) screening and surveillance in patients with cirrhosis or chronic hepatitis B virus (cHBV).

Materials And Methods: This was a retrospective study of consecutive patients aged 18 years and older with cirrhosis or cHBV who underwent at least one gadoxetate-enhanced abbreviated MRI examination for HCC surveillance from 2014 through 2016. Examinations were interpreted prospectively by one of six abdominal radiologists for clinical care.

The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens.

Background: The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function.

Results: Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes.