Atomistic Simulations of Polydisperse Lignin Melts Using Simple Polydisperse Residue Input Generator.

Understanding the physics of lignin will help rationalize its function in plant cell walls as well as aiding practical applications such as deriving biofuels and bioproducts. Here, we present SPRIG (Simple Polydisperse Residue Input Generator), a program for generating atomic-detail models of random polydisperse lignin copolymer melts i.e.

Water molecule ordering on the surface of an intrinsically disordered protein.

The dynamics and local structure of the hydration water on surfaces of folded proteins have been extensively investigated. However, our knowledge of the hydration of intrinsically disordered proteins (IDPs) is more limited. Here, we compare the local structure of water molecules hydrating a globular protein, lysozyme, and the intrinsically disordered N-terminal of c-Src kinase (SH4UD) using molecular dynamics simulation.

SCOMAP-XD: atomistic deuterium contrast matching for small-angle neutron scattering in biology.

The contrast-variation method in small-angle neutron scattering (SANS) is a uniquely powerful technique for determining the structure of individual components in biomolecular systems containing regions of different neutron scattering length density ρ. By altering the ρ of the target solute and the solvent through judicious incorporation of deuterium, the scattering of desired solute features can be highlighted. Most contrast-variation methods focus on highlighting specific bulk solute elements, but not on how the scattering at specific scattering vectors q, which are associated with specific structural distances, changes with contrast.

Disordered Domain Shifts the Conformational Ensemble of the Folded Regulatory Domain of the Multidomain Oncoprotein c-Src.

c-Src kinase is a multidomain non-receptor tyrosine kinase that aberrantly phosphorylates several signaling proteins in cancers. Although the structural properties of the regulatory domains (SH3-SH2) and the catalytic kinase domain have been extensively characterized, there is less knowledge about the N-terminal disordered region (SH4UD) and its interactions with the other c-Src domains. Here, we used domain-selective isotopic labeling combined with the small-angle neutron scattering contrast matching technique to study SH4UD interactions with SH3-SH2.

Dynamic odd-even effect in -alkane systems: a molecular dynamics study.

Alternation in various properties of -alkanes (CH) as a function of carbon content () is termed 'odd-even effect'. Here, we report a comprehensive molecular dynamics simulation study on -alkane systems carried out with ranging between 3 (propane) and 8 (octane), examining the odd-even effect in melting point, density, intramolecular conformational ordering, translational and rotational motion. We observe an odd-even alternation in these properties, but with heptane ( = 7) exhibiting anomalous behavior for all except conformational ordering.

Identification of Small-Molecule Inhibitors of Fibroblast Growth Factor 23 Signaling via In Silico Hot Spot Prediction and Molecular Docking to α-Klotho.

Fibroblast growth factor 23 (FGF23) is a therapeutic target for treating hereditary and acquired hypophosphatemic disorders, such as X-linked hypophosphatemic (XLH) rickets and tumor-induced osteomalacia (TIO), respectively. FGF23-induced hypophosphatemia is mediated by signaling through a ternary complex formed by FGF23, the FGF receptor (FGFR), and α-Klotho. Currently, disorders of excess FGF23 are treated with an FGF23-blocking antibody, burosumab.

Novel Small Molecule Fibroblast Growth Factor 23 Inhibitors Increase Serum Phosphate and Improve Skeletal Abnormalities in Mice.

Excess fibroblast growth factor (FGF) 23 causes hereditary hypophosphatemic rickets, such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO). A small molecule that specifically binds to FGF23 to prevent activation of the fibroblast growth factor receptor/-Klotho complex has potential advantages over the currently approved systemically administered FGF23 blocking antibody. Using structure-based drug design, we previously identified ZINC13407541 (N-[[2-(2-phenylethenyl)cyclopenten-1-yl]methylidene]hydroxylamine) as a small molecule antagonist for FGF23.

Full structural ensembles of intrinsically disordered proteins from unbiased molecular dynamics simulations.

Molecular dynamics (MD) simulation is widely used to complement ensemble-averaged experiments of intrinsically disordered proteins (IDPs). However, MD often suffers from limitations of inaccuracy. Here, we show that enhancing the sampling using Hamiltonian replica-exchange MD (HREMD) led to unbiased and accurate ensembles, reproducing small-angle scattering and NMR chemical shift experiments, for three IDPs of varying sequence properties using two recently optimized force fields, indicating the general applicability of HREMD for IDPs.

Deconstruction of biomass enabled by local demixing of cosolvents at cellulose and lignin surfaces.

A particularly promising approach to deconstructing and fractionating lignocellulosic biomass to produce green renewable fuels and high-value chemicals pretreats the biomass with organic solvents in aqueous solution. Here, neutron scattering and molecular-dynamics simulations reveal the temperature-dependent morphological changes in poplar wood biomass during tetrahydrofuran (THF):water pretreatment and provide a mechanism by which the solvent components drive efficient biomass breakdown. Whereas lignin dissociates over a wide temperature range (>25 °C) cellulose disruption occurs only above 150 °C.

Mesophilic Pyrophosphatase Function at High Temperature: A Molecular Dynamics Simulation Study.

The mesophilic inorganic pyrophosphatase from Escherichia coli (EcPPase) retains function at 353 K, the physiological temperature of hyperthermophilic Thermococcus thioreducens, whereas the homolog protein (TtPPase) from this hyperthermophilic organism cannot function at room temperature. To explain this asymmetric behavior, we examined structural and dynamical properties of the two proteins using molecular dynamics simulations. The global flexibility of TtPPase is significantly higher than its mesophilic homolog at all tested temperature/pressure conditions.

The relation between lignin sequence and its 3D structure.

Background: Lignin, the second most abundant biopolymer on earth, plays a major structural role in plants, conferring mechanical strength and regulating water conduction. Understanding the three-dimensional structure of lignin is important for fundamental reasons as well as engineering plants towards lignin valorization. Lignin lacks a specific primary sequence, making its average chemical composition the focus of most recent studies.

An Atomistic Molecular Dynamics Study of Titanium Dioxide Adhesion to Lipid Bilayers.

Titanium dioxide (TiO) nanoparticles are found in an array of consumer and industrial products, and human exposure to these nanoparticles involves interaction with biological membranes. To understand the effect of the membrane lipid composition on bilayer perturbation by TiO, we performed all-atom molecular dynamics simulations of nanosized TiO interacting with three single component bilayers differing only in their headgroup composition: the zwitterionic DOPC, which is overall neutral containing negatively charged phosphate and positively charged choline in its head, DOPG, which is overall anionic containing negatively charged phosphate and neutral glycerol, and the anionic DOPS, containing negatively charged phosphate attached to the hydroxyl side-chain of the amino acid, serine containing negatively charged carboxyl and positively charged ammonium. The nanoparticle adheres to all three bilayers causing a negative curvature on their top leaflet.

Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation.

Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes, play a major role in cell signaling, and are associated with human diseases. To understand IDP function it is critical to determine their configurational ensemble, i.e.

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.

A Multifunctional Cosolvent Pair Reveals Molecular Principles of Biomass Deconstruction.

The complex structure of plant cell walls resists chemical or biological degradation, challenging the breakdown of lignocellulosic biomass into renewable chemical precursors that could form the basis of future production of green chemicals and transportation fuels. Here, experimental and computational results reveal that the effect of the tetrahydrofuran (THF)-water cosolvents on the structure of lignin and on its interactions with cellulose in the cell wall drives multiple synergistic mechanisms leading to the efficient breakdown and fractionation of biomass into valuable chemical precursors. Molecular simulations show that THF-water is an excellent "theta" solvent, such that lignin dissociates from itself and from cellulose and expands to form a random coil.

Antimicrobial Zn-Based "TSOL" for Citrus Greening Management: Insights from Spectroscopy and Molecular Simulation.

Huanglongbing (HLB), also known as citrus greening, is a bacterial disease that poses a devastating threat to the citrus industry worldwide. To manage this disease efficiently, we developed and characterized a ternary aqueous solution (TSOL) that contains zinc nitrate, urea, and hydrogen peroxide. We report that TSOL exhibits better antimicrobial activity than commercial bactericides for growers.

Neutron scattering in the biological sciences: progress and prospects.

The scattering of neutrons can be used to provide information on the structure and dynamics of biological systems on multiple length and time scales. Pursuant to a National Science Foundation-funded workshop in February 2018, recent developments in this field are reviewed here, as well as future prospects that can be expected given recent advances in sources, instrumentation and computational power and methods. Crystallography, solution scattering, dynamics, membranes, labeling and imaging are examined.

Dynamics of the lignin glass transition.

The dynamics of lignin, a complex and heterogeneous major plant cell-wall macromolecule, is of both fundamental and practical importance. Lignin is typically heated to temperatures above its glass transition to facilitate its industrial processing. We performed molecular dynamics simulations to investigate the segmental (α) relaxation of lignin, the dynamical process that gives rise to the glass transition.

Quantum Calculations on Plant Cell Wall Component Interactions.

Density functional theory calculations were performed to assess the relative interaction energies of plant cell wall components: cellulose, xylan, lignin and pectin. Monomeric and tetramer linear molecules were allowed to interact in four different configurations for each pair of compounds. The M05-2X exchange-correlation functional which implicitly accounts for short- and mid-range dispersion was compared against MP2 and RI-MP2 to assess the reliability of the former for modeling van der Waals forces between these PCW components.

Dynamic Neutron Scattering by Biological Systems.

Dynamic neutron scattering directly probes motions in biological systems on femtosecond to microsecond timescales. When combined with molecular dynamics simulation and normal mode analysis, detailed descriptions of the forms and frequencies of motions can be derived. We examine vibrations in proteins, the temperature dependence of protein motions, and concepts describing the rich variety of motions detectable using neutrons in biological systems at physiological temperatures.

Relationship between lignocellulosic biomass dissolution and physicochemical properties of ionic liquids composed of 3-methylimidazolium cations and carboxylate anions.

The ionic liquid (IL) 1-ethyl-3-methylimidazolium acetate ([EMIM]Acetate) has been widely used for biomass processing, i.e., to pretreat, activate, or fractionate lignocellulosic biomass to produce soluble sugars and lignin.

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.

Dynamics of water bound to crystalline cellulose.

Interactions of water with cellulose are of both fundamental and technological importance. Here, we characterize the properties of water associated with cellulose using deuterium labeling, neutron scattering and molecular dynamics simulation. Quasi-elastic neutron scattering provided quantitative details about the dynamical relaxation processes that occur and was supported by structural characterization using small-angle neutron scattering and X-ray diffraction.