Iterative model-building, structure refinement, and density modification with the PHENIX AutoBuild Wizard Thomas C. Terwilliger a* , Ralf W. Grosse-Kunstleve b , Pavel V. Afonine b , Nigel W. Moriarty b , Peter Zwart b , Li-Wei Hung a , Randy J. Read c , Paul D. Adams b* a b Los Alamos National Laboratory, Mailstop M888, Los Alamos, NM 87545, USA Lawrence Berkeley National Laboratory, One Cyclotron Road, Bldg 64R0121, Berkeley, CA 94720, USA. c Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK. * Email: terwill@lanl.gov or PDAdams@lbl.gov Running title: The PHENIX AutoBuild Wizard Abstract The PHENIX AutoBuild Wizard is a highly automated tool for iterative model- building, structure refinement and density modification using RESOLVE or TEXTAL model- building, RESOLVE statistical density modification, and phenix.refine structure refinement. Recent advances in the AutoBuild Wizard and phenix.refine include automated detection and application of NCS from models as they are built, extensive model completion algorithms, and automated solvent molecule picking. Model completion algorithms in the AutoBuild Wizard include loop-building, crossovers between chains in different models of a structure, and side-chain optimization. The AutoBuild Wizard has been applied to a set of 48 structures at resolutions ranging from 1.1 A to 3.2 A, resulting in a mean R-factor of 0.24 and a mean free R factor of 0.29. The R-factor of the final model is dependent on the quality of the starting electron density, and relatively independent of resolution. Keywords: Model building; model completion; macromolecular models; Protein Data Bank; structure refinement; PHENIX Introduction Iterative model-building and refinement is a powerful approach to obtaining a complete and accurate macromolecular model. The approach consists of cycles of building an atomic model based on an electron density map for a macromolecular structure, refining the structure, using the refined structure as a basis for improving the map, and building a new model. This type of approach has been carried out in a semi-automated fashion for many years, with manual model-building iterating with automated refinement (Jensen, 1997). More recently, with the development first of ARP/wARP (Perrakis et al., 1999), and later other procedures including RESOLVE iterative model-building and refinement (Terwilliger,

Iterative model-building, structure refinement, and density modification with the PHENIX AutoBuild Wizard

The rapid development of drug nanocarriers has benefited from the surface hydrophilic polymers of particles, which has improved the pharmacokinetics of the drugs. Polyethylene glycol (PEG) is a kind of polymeric material with unique hydrophilicity and electrical neutrality. PEG coating is a crucial factor to improve the biophysical and chemical properties of nanoparticles and is widely studied. Protein adherence and macrophage removal are effectively relieved due to the existence of PEG on the particles. This review discusses the PEGylation methods of nanoparticles and related techniques that have been used to detect the PEG coverage density and thickness on the surface of the nanoparticles in recent years. The molecular weight (MW) and coverage density of the PEG coating on the surface of nanoparticles are then described to explain the effects on the biophysical and chemical properties of nanoparticles.

/pdf/effects-of-polyethylene-glycol-on-the-surface-of-gfy3iauaul.pdf

Effects of polyethylene glycol on the surface of nanoparticles for targeted drug delivery

Polyethylene glycol (PEG) is a flexible, hydrophilic simple polymer that is physically attached to peptides, proteins, nucleic acids, liposomes, and nanoparticles to reduce renal clearance, block antibody and protein binding sites, and enhance the half-life and efficacy of therapeutic molecules. Some naive individuals have pre-existing antibodies that can bind to PEG, and some PEG-modified compounds induce additional antibodies against PEG, which can adversely impact drug efficacy and safety. Here we provide a framework to better understand PEG immunogenicity and how antibodies against PEG affect pegylated drug and nanoparticles. Analysis of published studies reveals rules for predicting accelerated blood clearance of pegylated medicine and therapeutic liposomes. Experimental studies of anti-PEG antibody binding to different forms, sizes, and immobilization states of PEG are also provided. The widespread use of SARS-CoV-2 RNA vaccines that incorporate PEG in lipid nanoparticles make understanding possible effects of anti-PEG antibodies on pegylated medicines even more critical.

Polyethylene Glycol Immunogenicity: Theoretical, Clinical, and Practical Aspects of Anti-Polyethylene Glycol Antibodies.

• Jess chose a study because it was likely to be scaled up, but she was not very interested or strong at it. She got a VCE study score of 25 for the study, which was scaled up to an ATAR subject score of 29. This was lower than the rest of her VTAC Scaled Study scores, all scaled down to between 32 and 34. Jess would have been better off choosing all her studies based on her interests and strengths. • Morgan on the other hand chose all his studies based on his strengths and interests. Morgan still selected two studies that were scaled down, but got VCE study scores of 38 for one and 40 for the other. These were scaled down to 36 and 39 respectively. These were about the same as the rest of Morgan’s VTAC Scaled Study scores, which were around 38 to 39. Morgan was not disadvantaged by choosing those studies.

Facts and Fiction

Zwitterionic polydopamine modified nanoparticles as an efficient nanoplatform to overcome both the mucus and epithelial barriers

Polyethylene glycol (PEG) is a polymer routinely used to modify biologics and nanoparticles to prolong blood circulation and reduce immunogenicity of the underlying therapeutic. However, several PEGylated therapeutics induce the development of anti-PEG antibodies (APA), leading to reduced efficacy and increased adverse events. Given the highly flexible structure of PEG, how APA specifically bind PEG remains poorly understood. Here, we report a crystal structure illustrating the structural properties and conformation of the APA 6-3 Fab bound to the backbone of PEG. The structure reveals an open ring-like sub-structure in the Fab paratope, whereby PEG backbone is captured and then stabilized via Van der Waals interactions along the interior and exterior of the ring paratope surface. Our finding illustrates a strategy by which antibodies can bind highly flexible repeated structures that lack fixed conformations, such as polymers. This also substantially advances our understanding of the humoral immune response generated against PEG. Polyethylene glycol (PEG) is a widely used, biocompatible material, but can promote the development of anti-PEG antibodies. Here, crystal structures of an anti-PEG antibody binding fragment bound to PEG are reported and key binding residues are identified by site-directed mutagenesis.

/pdf/structure-of-an-anti-peg-antibody-reveals-an-open-ring-that-2l7bolgs4a.pdf

Structure of an anti-PEG antibody reveals an open ring that captures highly flexible PEG polymers

Mucus represents a major barrier to sustained and targeted drug delivery to mucosal epithelium. Ideal drug carriers should not only rapidly diffuse across mucus, but also bind the epithelium. Unfortunately, ligand-conjugated particles often exhibit poor penetration across mucus. In this work, we explored a two-step "pretargeting" approach through engineering a bispecific antibody that binds both cell-surface ICAM-1 and polyethylene glycol (PEG) on the surface of nanoparticles, thereby effectively decoupling cell targeting from particle design and formulation. When tested in a mucus-coated Caco-2 culture model that mimics the physiological process of mucus clearance, pretargeting increased the amount of PEGylated particles binding to cells by around 2-fold or more compared to either non-targeted or actively targeted PEGylated particles. Pretargeting also markedly enhanced particle retention in mouse intestinal tissues. Our work underscores pretargeting as a promising strategy to improve the delivery of therapeutics to mucosal surfaces.

Engineering Polymer-Binding Bispecific Antibodies for Enhanced Pretargeted Delivery of Nanoparticles to Mucus-Covered Epithelium.

The question of at what resolution the large eddy simulations (LESs) of a tropical cyclone (TC) high wind area may converge largely remains unanswered. To address this issue, LESs with five resolutions of 300 m, 100 m, 60 m, 33 m, and 20 m are performed in this study to simulate a high wind area near the radius of maximum wind of Typhoon Chanthu (2021) using the Weather Research and Forecasting (WRF) model. The results show that, for a limited area LES, model grid resolution may alter the local turbulence structure to generate significantly different extreme values of temperature, moisture, and winds, but it only has a marginal impact on the median values of these variables throughout the vertical column. All simulations are able to capture the turbulent roll vortices in the TC boundary layer, but the structure and intensity of the rolls vary substantially in different resolution simulations. Local hectometer-scale eddies with vertical velocities exceeding 10 m s−1 are only observed in the 20 m resolution simulation but not in the coarser resolution simulations. The ratio of the resolved turbulent momentum fluxes and turbulent kinetic energies (TKEs) to the total momentum fluxes and TKEs appears to show some convergence of LESs when the grid resolution reaches 100 m or finer, suggesting that it is an acceptable grid resolution for LES applications in TC simulations. 

The Sensitivity of Large Eddy Simulations to Grid Resolution in Tropical Cyclone High Wind Area Applications

Organic aerosols are harmful to the environment because of their impact on air quality and visibility. They have serious effects not only on living beings and ecosystems because of their biological toxicity, but they also have an indirect effect on regional climate change as cloud condensation nuclei and radiation force. Many measures have been applied to decrease air pollution. Although the air quality has greatly improved, the standard of the World Health Organization (WHO) is far from being met at present. In this study, fine particulates were collected in Nanjing throughout 2019, and high-performance liquid chromatography–electrospray ion–mass spectrometry/mass spectrometry (HPLC-ESI-MS/MS) was carried out to determine 14 organic acids, 10 nitrated phenols, 1 aldehyde, and 1 ketone in aerosol samples. In this study, we further determined the changes in the pollutants in Nanjing in recent years compared to previous studies and characterized more kinds of species in the air. We found that different kinds of nitrated phenols showed similar trends of being abundant in winter and substituted in spring, autumn, and summer. 4-Nitrophenol was the most abundant species (2.83 ng m−3) among the nitrated phenols. p-Coumaric acid presented the highest level in summer with an average concentration of 1.55 ng m−3, indicating that grass burning was significant in summer, possibly due to wheat stalk and perennial ryegrass burning. The positive matrix fraction (PMF) model was applied to identify the sources of aerosols in Nanjing, including coal burning, grass burning, softwood burning, hardwood burning, anthropogenic secondary organic aerosols (SOAs), and biogenic SOAs. Coal burning and softwood burning contributed much more to the total determined species with values of 20.3% and 18.2%, respectively. Anthropogenic SOAs contributed 17.1%, and hardwood burning contributed 16.7%. The contribution of biogenic SOAs was 15%, and the grass-burning source contribution was the lowest, with 12.6%. With consideration of the large contribution from anthropogenic combustion activities, more strict measures are required to reduce emission pollutants in the future.

/pdf/compositions-and-sources-of-organic-aerosol-in-pm2-5-in-2t9hh89t.pdf

Compositions and Sources of Organic Aerosol in PM2.5 in Nanjing in China

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Structure of an anti-PEG antibody reveals an open ring that captures highly flexible PEG polymers

Engineering Polymer-Binding Bispecific Antibodies for Enhanced Pretargeted Delivery of Nanoparticles to Mucus-Covered Epithelium.

The Sensitivity of Large Eddy Simulations to Grid Resolution in Tropical Cyclone High Wind Area Applications

Compositions and Sources of Organic Aerosol in PM2.5 in Nanjing in China