Toxic Effects of Butanol in the Plane of the Cell Membrane.

Solvent toxicity limits -butanol fermentation titer, increasing the cost and energy consumption for subsequent separation processes and making biobased production more expensive and energy-intensive than petrochemical approaches. Amphiphilic solvents such as -butanol partition into the cell membrane of fermenting microorganisms, thinning the transverse structure, and eventually causing a loss of membrane potential and cell death. In this work, we demonstrate the deleterious effects of -butanol partitioning upon the lateral dimension of the membrane structure, called membrane domains or lipid rafts.

GPRC6A is a Potential Therapeutic Target for Metformin Regulation of Glucose Homeostasis in Mice.

Understanding the mechanism of metformin actions in treating type 2 diabetes is limited by an incomplete knowledge of the specific protein targets mediating its metabolic effects. Metformin has structural similarities to L-Arginine (2-amino-5-guanidinopentanoic acid), which is a ligand for GPRC6A, a Family C G-protein coupled receptor that regulates energy metabolism. Ligand activation of GPRC6A results in lowering of blood glucose and other metabolic changes resembling the therapeutic effect of metformin.

Chromosome compartmentalization: causes, changes, consequences, and conundrums.

The spatial segregation of the genome into compartments is a major feature of 3D genome organization. New data on mammalian chromosome organization across different conditions reveal important information about how and why these compartments form and change. A combination of epigenetic state, nuclear body tethering, physical forces, gene expression, and replication timing (RT) can all influence the establishment and alteration of chromosome compartments.

Drugging the entire human proteome: Are we there yet?

Each of the ∼20,000 proteins in the human proteome is a potential target for compounds that bind to it and modify its function. The 3D structures of most of these proteins are now available. Here, we discuss the prospects for using these structures to perform proteome-wide virtual HTS (VHTS).

Variable lignin structure revealed in leaves.

Lignin has long been a trait of interest, especially in bioenergy feedstocks such as . While the stem lignin of is well studied, foliar lignin has received significantly less consideration. To this end, leaves from 11 field grown, natural variant genotypes were investigated by NMR, FTIR, and GC-MS.

Dissecting Phenotype from Genotype with Clinical Isolates of SARS-CoV-2 First Wave Variants.

The emergence and availability of closely related clinical isolates of SARS-CoV-2 offers a unique opportunity to identify novel nonsynonymous mutations that may impact phenotype. Global sequencing efforts show that SARS-CoV-2 variants have emerged and then been replaced since the beginning of the pandemic, yet we have limited information regarding the breadth of variant-specific host responses. Using primary cell cultures and the K18-hACE2 mouse, we investigated the replication, innate immune response, and pathology of closely related, clinical variants circulating during the first wave of the pandemic.

Origins of glycan selectivity in streptococcal Siglec-like adhesins suggest mechanisms of receptor adaptation.

Bacterial binding to host receptors underlies both commensalism and pathogenesis. Many streptococci adhere to protein-attached carbohydrates expressed on cell surfaces using Siglec-like binding regions (SLBRs). The precise glycan repertoire recognized may dictate whether the organism is a strict commensal versus a pathogen.

Peptide nucleic acid Hoogsteen strand linker design for major groove recognition of DNA thymine bases.

Sequence-specific targeting of double-stranded DNA and non-coding RNA via triple-helix-forming peptide nucleic acids (PNAs) has attracted considerable attention in therapeutic, diagnostic and nanotechnological fields. An E-base (3-oxo-2,3-dihydropyridazine), attached to the polyamide backbone of a PNA Hoogsteen strand by a side-chain linker molecule, is typically used in the hydrogen bond recognition of the 4-oxo group of thymine and uracil nucleic acid bases in the major groove. We report on the application of quantum chemical computational methods, in conjunction with spatial constraints derived from the experimental structure of a homopyrimidine PNA·DNA-PNA hetero-triplex, to investigate the influence of linker flexibility on binding interactions of the E-base with thymine and uracil bases in geometry-optimised model systems.

Prediction of peptide binding to MHC using machine learning with sequence and structure-based feature sets.

Selecting peptides that bind strongly to the major histocompatibility complex (MHC) for inclusion in a vaccine has therapeutic potential for infections and tumors. Machine learning models trained on sequence data exist for peptide:MHC (p:MHC) binding predictions. Here, we train support vector machine classifier (SVMC) models on physicochemical sequence-based and structure-based descriptor sets to predict peptide binding to a well-studied model mouse MHC I allele, H-2D.

Using Small-Angle Scattering Data and Parametric Machine Learning to Optimize Force Field Parameters for Intrinsically Disordered Proteins.

Intrinsically disordered proteins (IDPs) and proteins with intrinsically disordered regions (IDRs) play important roles in many aspects of normal cell physiology, such as signal transduction and transcription, as well as pathological states, including Alzheimer's, Parkinson's, and Huntington's disease. Unlike their globular counterparts that are defined by a few structures and free energy minima, IDP/IDR comprise a large ensemble of rapidly interconverting structures and a corresponding free energy landscape characterized by multiple minima. This aspect has precluded the use of structural biological techniques, such as X-ray crystallography and nuclear magnetic resonance (NMR) for resolving their structures.

Integration of renewable deep eutectic solvents with engineered biomass to achieve a closed-loop biorefinery.

Despite the enormous potential shown by recent biorefineries, the current bioeconomy still encounters multifaceted challenges. To develop a sustainable biorefinery in the future, multidisciplinary research will be essential to tackle technical difficulties. Herein, we leveraged a known plant genetic engineering approach that results in aldehyde-rich lignin via down-regulation of cinnamyl alcohol dehydrogenase () and disruption of monolignol biosynthesis.

Environmental Mercury Chemistry - In Silico.

Mercury (Hg) is a global environmental contaminant. Major anthropogenic sources of Hg emission include gold mining and the burning of fossil fuels. Once deposited in aquatic environments, Hg can undergo redox reactions, form complexes with ligands, and adsorb onto particles.

Quantum Mechanical/Molecular Mechanical Analysis of the Catalytic Mechanism of Phosphoserine Phosphatase.

Phosphoserine phosphatase (PSP), a member of the haloacid dehalogenase (HAD) superfamily that comprises the vast majority of phosphotransferases, is likely a steady-state regulator of the level of d-serine in the brain. The proposed catalytic cycle of PSP consists of a two-step mechanism: formation of a phospho-enzyme intermediate by phosphate transfer to Asp11 and its subsequent hydrolysis. Our combined quantum mechanical/molecular mechanical (QM/MM) calculations of the reaction pathways favour a dissociative mechanism of nucleophilic substitution via a trigonal-planar metaphosphate-like configuration for both steps, associated with proton transfer to the leaving group or from the nucleophile.

Degradation of hydraulic fracturing additive 2-butoxyethanol using heat activated persulfate in the presence of shale rock.

Changes in fluid composition during hydraulic fracturing (HF) for natural gas production can impact well productivity and the water quality of the fluids returning to the surface during productivity. Shale formation conditions can influence the extent of fluid transformation. Oxidizers, such as sodium persulfate, likely play a strong role in fluid transformation.

A low-barrier hydrogen bond mediates antibiotic resistance in a noncanonical catalytic triad.

One group of enzymes that confer resistance to aminoglycoside antibiotics through covalent modification belongs to the GCN5-related -acetyltransferase (GNAT) superfamily. We show how a unique GNAT subfamily member uses a previously unidentified noncanonical catalytic triad, consisting of a glutamic acid, a histidine, and the antibiotic substrate itself, which acts as a nucleophile and attacks the acetyl donor molecule. Neutron diffraction studies allow for unambiguous identification of a low-barrier hydrogen bond, predicted in canonical catalytic triads to increase basicity of the histidine.

Development and Validation of Personality Disorder Spectra Scales for the MMPI-2-RF.

The purpose of this study was to develop and validate a set of MMPI-2-RF (Ben-Porath & Tellegen, 2008/2011) personality disorder (PD) spectra scales. These scales could serve the purpose of assisting with DSM-5 PD diagnosis and help link categorical and dimensional conceptions of personality pathology within the MMPI-2-RF. We developed and provided initial validity results for scales corresponding to the 10 PD constructs listed in the DSM-5 using data from student, community, clinical, and correctional samples.

Graduate Training at the Interface of Computational and Experimental Biology: An Outcome Report from a Partnership of Volunteers between a University and a National Laboratory.

Leading voices in the biological sciences have called for a transformation in graduate education leading to the PhD degree. One area commonly singled out for growth and innovation is cross-training in computational science. In 1998, the University of Tennessee (UT) founded an intercollegiate graduate program called the UT-ORNL Graduate School of Genome Science and Technology in partnership with the nearby Oak Ridge National Laboratory.

Organosolv-Water Cosolvent Phase Separation on Cellulose and its Influence on the Physical Deconstruction of Cellulose: A Molecular Dynamics Analysis.

Deconstruction of cellulose is crucial for the chemical conversion of lignocellulose into fuel/bioproduct precursors. Recently, a water-organosolv cosolvent system (THF-water) has been shown to both phase-separate on cellulose surfaces and partially deconstruct Avicel  (cellulose) in the absence of acid. Here we employ molecular dynamics simulations to determine whether other common water-organosolv cosolvent systems (acetone, ethanol, and γ-valerolactone) exhibit phase separation at cellulose surface and whether this alters a purely physical cellulose dissociation pathway.

Community detection in sequence similarity networks based on attribute clustering.

Networks are powerful tools for the presentation and analysis of interactions in multi-component systems. A commonly studied mesoscopic feature of networks is their community structure, which arises from grouping together similar nodes into one community and dissimilar nodes into separate communities. Here, the community structure of protein sequence similarity networks is determined with a new method: Attribute Clustering Dependent Communities (ACDC).

Protonation-state-Coupled Conformational Dynamics in Reaction Mechanisms of Channel and Pump Rhodopsins.

Channel and pump rhodopsins use energy from light absorbed by a covalently bound retinal chromophore to transport ions across membranes of microbial cells. Ion transfer steps, including proton transfer, can couple to changes in protein conformational dynamics and water positions. Although general principles of how microbial rhodopsins function are largely understood, key issues pertaining to reaction mechanisms remain unclear.

Direct evidence that an extended hydrogen-bonding network influences activation of pyridoxal 5'-phosphate in aspartate aminotransferase.

Pyridoxal 5'-phosphate (PLP) is a fundamental, multifunctional enzyme cofactor used to catalyze a wide variety of chemical reactions involved in amino acid metabolism. PLP-dependent enzymes optimize specific chemical reactions by modulating the electronic states of PLP through distinct active site environments. In aspartate aminotransferase (AAT), an extended hydrogen bond network is coupled to the pyridinyl nitrogen of the PLP, influencing the electrophilicity of the cofactor.