| 1. |
- Andersson, Jenny Marie, et al.
(författare)
-
The Impact of Nonequilibrium Conditions in Lung Surfactant : Structure and Composition Gradients in Multilamellar Films
- 2018
-
Ingår i: ACS Central Science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 4:10, s. 1315-1325
-
Tidskriftsartikel (refereegranskat)abstract
- The lipid-protein mixture that covers the lung alveoli, lung surfactant, ensures mechanical robustness and controls gas transport during breathing. Lung surfactant is located at an interface between water-rich tissue and humid, but not fully saturated, air. The resulting humidity difference places the lung surfactant film out of thermodynamic equilibrium, which triggers the buildup of a water gradient. Here, we present a millifluidic method to assemble multilamellar interfacial films from vesicular dispersions of a clinical lung surfactant extract used in replacement therapy. Using small-angle X-ray scattering, infrared, Raman, and optical microscopies, we show that the interfacial film consists of several coexisting lamellar phases displaying a substantial variation in water swelling. This complex phase behavior contrasts to observations made under equilibrium conditions. We demonstrate that this disparity stems from additional lipid and protein gradients originating from differences in their transport properties. Supplementing the extract with cholesterol, to levels similar to the endogenous lung surfactant, dispels this complexity. We observed a homogeneous multilayer structure consisting of a single lamellar phase exhibiting negligible variations in swelling in the water gradient. Our results demonstrate the necessity of considering nonequilibrium thermodynamic conditions to study the structure of lung surfactant multilayer films, which is not accessible in bulk or monolayer studies. Our reconstitution methodology also opens avenues for lung surfactant pharmaceuticals and the understanding of composition, structure, and property relationships at biological air-liquid interfaces.
|
|
| 2. |
- Aspuru-Guzik, Alan, et al.
(författare)
-
The Matter Simulation (R)evolution
- 2018
-
Ingår i: ACS CENTRAL SCIENCE. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 4:2, s. 144-152
-
Tidskriftsartikel (refereegranskat)abstract
- To date, the program for the development of methods and models for atomistic and continuum simulation directed toward chemicals and materials has reached an incredible degree of sophistication and maturity. Currently, one can witness an increasingly rapid emergence of advances in computing, artificial intelligence, and robotics. This drives us to consider the future of computer simulation of matter from the molecular to the human length and time scales in a radical way that deliberately dares to go beyond the foreseeable next steps in any given discipline. This perspective article presents a view on this future development that we believe is likely to become a reality during our lifetime.
|
|
| 3. |
- Bosque, Irene, et al.
(författare)
-
Redox Catalysis Facilitates Lignin Depolymerization
- 2017
-
Ingår i: ACS Central Science. - : American Chemical Society (ACS). - 2374-7951 .- 2374-7943. ; 3:6, s. 621-628
-
Tidskriftsartikel (refereegranskat)abstract
- Lignin is a recalcitrant and underexploited natural feedstock for aromatic commodity chemicals, and its degradation generally requires the use of high temperatures and harsh reaction conditions. Herein we present an ambient temperature one-pot process for the controlled oxidation and depolymerization of this potent resource. Harnessing the potential of electrocatalytic oxidation in conjugation with our photocatalytic cleavage methodology, we have developed an operationally simple procedure for selective fragmentation of β-O-4 bonds with excellent mass recovery, which provides a unique opportunity to expand the existing lignin usage from energy source to commodity chemicals and synthetic building block source.
|
|
| 4. |
- Emilsson, Gustav, 1989, et al.
(författare)
-
Gating Protein Transport in Solid State Nanopores by Single Molecule Recognition
- 2018
-
Ingår i: ACS Central Science. - : American Chemical Society (ACS). - 2374-7951 .- 2374-7943. ; 4:8, s. 1007-1014
-
Tidskriftsartikel (refereegranskat)abstract
- Control of molecular translocation through nanoscale apertures is of great interest for DNA sequencing, biomolecular filters, and new platforms for single molecule analysis. However, methods for controlling the permeability of nanopores are very limited. Here, we show how nanopores functionalized with poly(ethylene glycol) brushes, which fully prevent protein translocation, can be reversibly gated to an "open" state by binding of single IgG antibodies that disrupt the macromolecular barrier. On the basis of surface plasmon resonance data we propose a two-state model describing the antibody-polymer interaction kinetics. Reversibly (weakly) bound antibodies decrease the protein exclusion height while irreversibly (strongly) bound antibodies do not. Our results are further supported by fluorescence readout from pore arrays and high-speed atomic force microscopy on single pores. This type of dynamic barrier control on the nanoscale provides new possibilities for biomolecular separation and analysis.
|
|
| 5. |
- Gemmi, Mauro, et al.
(författare)
-
3D Electron Diffraction : The Nanocrystallography Revolution
- 2019
-
Ingår i: ACS central science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 5:8, s. 1315-1329
-
Tidskriftsartikel (refereegranskat)abstract
- Crystallography of nanocrystalline materials has witnessed a true revolution in the past 10 years, thanks to the introduction of protocols for 3D acquisition and analysis of electron diffraction data. This method provides single-crystal data of structure solution and refinement quality, allowing the atomic structure determination of those materials that remained hitherto unknown because of their limited crystallinity. Several experimental protocols exist, which share the common idea of sampling a sequence of diffraction patterns while the crystal is tilted around a noncrystallographic axis, namely, the goniometer axis of the transmission electron microscope sample stage. This Outlook reviews most important 3D electron diffraction applications for different kinds of samples and problematics, related with both materials and life sciences. Structure refinement including dynamical scattering is also briefly discussed.
|
|
| 6. |
- Gentile, Francesco, et al.
(författare)
-
Deep Docking : A Deep Learning Platform for Augmentation of Structure Based Drug Discovery
- 2020
-
Ingår i: ACS central science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 6:6, s. 939-949
-
Tidskriftsartikel (refereegranskat)abstract
- Drug discovery is a rigorous process that requires billion dollars of investments and decades of research to bring a molecule from bench to a bedside. While virtual docking can significantly accelerate the process of drug discovery, it ultimately lags the current rate of expansion of chemical databases that already exceed billions of molecular records. This recent surge of small molecules availability presents great drug discovery opportunities, but also demands much faster screening protocols. In order to address this challenge, we herein introduce Deep Docking (DD), a novel deep learning platform that is suitable for docking billions of molecular structures in a rapid, yet accurate fashion. The DD approach utilizes quantitative structure-activity relationship (QSAR) deep models trained on docking scores of subsets of a chemical library to approximate the docking outcome for yet unprocessed entries and, therefore, to remove unfavorable molecules in an iterative manner. The use of DD methodology in conjunction with the FRED docking program allowed rapid and accurate calculation of docking scores for 1.36 billion molecules from the ZINC15 library against 12 prominent target proteins and demonstrated up to 100-fold data reduction and 6000-fold enrichment of high scoring molecules (without notable loss of favorably docked entities). The DD protocol can readily be used in conjunction with any docking program and was made publicly available.
|
|
| 7. |
- Guimond, S. E., et al.
(författare)
-
Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction
- 2022
-
Ingår i: ACS Central Science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 8:5, s. 527-545
-
Tidskriftsartikel (refereegranskat)abstract
- Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.
|
|
| 8. |
|
|
| 9. |
- Huang, Xiaofeng, et al.
(författare)
-
Solvent Gaming Chemistry to Control the Quality of Halide Perovskite Thin Films for Photovoltaics
- 2022
-
Ingår i: ACS CENTRAL SCIENCE. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 8:7, s. 1008-1016
-
Tidskriftsartikel (refereegranskat)abstract
- Research on solvent chemistry, particularly for halide perovskite intermediates, has been advancing the development of perovskite solar cells (PSCs) toward commercial applications. A predictive understanding of solvent effects on the perovskite formation is thus essential. This work systematically discloses the relationship among the basicity of solvents, solvent-contained intermediate structures, and intermediate-to-perovskite alpha-FAPbI(3) evolutions. Depending on their basicity, solvents exhibit their own favorite bonding selection with FA(+) or Pb2+ cations by forming either hydrogen bonds or coordination bonds, resulting in two different kinds of intermediate structures. While both intermediates can be evolved into alpha-FAPbI(3) below the delta-to-alpha thermodynamic temperature, the hydrogen-bond-favorable kind could form defect-less alpha-FAPbI(3) via sidestepping the break of strong coordination bonds. The disclosed solvent gaming mechanism guides the solvent selection for fabricating high-quality perovskite films and thus high-performance PSCs and modules.
|
|
| 10. |
- Huang, Xiaoli, et al.
(författare)
-
The Molecular Basis for Inhibition of Stemlike Cancer Cells by Salinomycin
- 2018
-
Ingår i: ACS Central Science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 4:6, s. 760-767
-
Tidskriftsartikel (refereegranskat)abstract
- Tumors are phenotypically heterogeneous and include subpopulations of cancer cells with stemlike properties. The natural product salinomycin, a K+-selective ionophore, was recently found to exert selectivity against such cancer stem cells. This selective effect is thought to be due to inhibition of the Wnt signaling pathway, but the mechanistic basis remains unclear. Here, we develop a functionally competent fluorescent conjugate of salinomycin to investigate the molecular mechanism of this compound. By subcellular imaging, we demonstrate a rapid cellular uptake of the conjugate and accumulation in the endoplasmic reticulum (ER). This localization is connected to induction of Ca2+ release from the ER into the cytosol. Depletion of Ca2+ from the ER induces the unfolded protein response as shown by global mRNA analysis and Western blot analysis of proteins in the pathway. In particular, salinomycin-induced ER Ca2+ depletion up-regulates C/EBP homologous protein (CHOP), which inhibits Wnt signaling by down-regulating β-catenin. The increased cytosolic Ca2+ also activates protein kinase C, which has been shown to inhibit Wnt signaling. These results reveal that salinomycin acts in the ER membrane of breast cancer cells to cause enhanced Ca2+ release into the cytosol, presumably by mediating a counter-flux of K+ ions. The clarified mechanistic picture highlights the importance of ion fluxes in the ER as an entry to inducing phenotypic effects and should facilitate rational development of cancer treatments.
|
|
