Projects & Collaborations 6 foundShow per page10 10 20 50 Biomolecules in motion: Electron diffraction studies of native protein samples in graphene liquid cells. Research Project | 1 Project MembersNo Description available Single molecule electron diffraction Research Project | 4 Project MembersI propose establishing a technology platform for validating single molecule electron diffraction (simED) as an alternative, general method for structural studies of dynamic biomolecular complexes at atomic resolution. There is significant evidence that simED could boost the low signal-to-noise ratio of cryo-EM single particle analysis by an order of magnitude or more, potentially allowing structural studies beyond current capabilities and extending resolution in ongoing projects. The proposal plans developing simED by implementing unique instrumentation, automated data collection protocols and exploring phasing methods from protein crystallography. This development of hardware, software and automated data collection protocols also strongly supports nano-crystallographic applications, including pre-screening of nanocrystals for SwissFEL, polymorph screening in pharmaceutical research and further development of protein nanocrystallography within the EU-funded innovative training network "NaNED" (https://cordis.europa.eu/project/id/956099) kicking off in 2021. The proposal links the development of an advanced technology platform to the elucidation of important, fundamental process of life. Linking these goals ensures that the development of simED addresses real needs in biological research. The proposal builds upon the results of my previous SNF project grant, that focused on developing electron diffraction of crystalline samples for structural biology. In the last few years, electron crystallography became an established method for atomic structure determination. In September 2020, Basel University purchased an electron microscope for developing simED technology (delivery: spring 2021), that will initially be located at the PSI. It will be enhanced with a commercial post-column energy filter and a PSI JUNGFRAU direct electron detector. The new equipment is funded jointly by Basel University and the PSI and fully dedicated to electron diffraction studies, including the development of simED. It falls under responsibility of my joint research group located at these two institutions. If simED cannot produce data of the required quality, we will implement and further investigate cryo-electron ptychography using defocused convergent beam diffraction. This novel application in cryo-EM was published in June 2020 (Zhou, L et al. "Low-dose phase retrieval of biological specimens using cryo-electron ptychography". Nat Commun 11, 2773 (2020)). Like in simED, this method scans the sample with a narrow beam, but this beam is convergent, and the diffraction data are measured as highly defocused images, whereas in simED the beam is essentially parallel, and the data are measured in the far field. The simED infrastructure can support both methods optimally. Following ideas developed at the LMB by Russo and colleagues, we will also explore simED at lower electron energies, as this may further boost the signal-to-noise ration by reducing radiation damage by up to 25%. As a second backup, we will consider implementing single particle cryo-EM imaging at lower energy on our simED instrumentation. Sample optimization, theory, algorithms and software concepts developed in the course of this project may contribute to extending the resolution of single molecule XFEL X-ray diffraction beyond its current limits of approximately 100 nm. NanED / Electron Nanocrystallography Research Project | 1 Project MembersThe atomic structure determination of inorganic, organic and macromolecular compounds is a hard challenge anytime the crystal size falls below the micron range, becoming no more suitable for single-crystal x-ray diffraction. Still, a number of chemicals with valuable commercial and medical implications can be synthesized only as nanocrystals or show phase/ polymorphic transitions during crystal growth. The development of more efficient tools able to disclose the nature of nanocrystalline materials is therefore a hot and transversal topic that links materials science, physics of diffraction, new instrument engineering, chemical production and pharmacology. Electron diffraction (ED) allows extracting structure information from single nanometric crystals. ED experienced a tremendous boost after the development of 3D routines for data collection, up to be enlisted among the main breakthroughs in Science. However, the development of 3D ED is still limited to few laboratories and is slowed by the lack of dedicated instrumentation. NanED aims to form a new generation of electron crystallographers, able to master and develop 3D ED techniques in an interdisciplinary and interconnected network, where competences and know-how of usually distant scientific sectors are shared and merged. NanED will gather all European scientists hitherto active in 3D ED development and a pool of large and small companies interested in instrument development and material or pharmaceutical production. NanED will deliver portable procedures for sample preparation, data collection and data analysis, suitable for the successful application of 3D ED to all kinds of compounds. NanED will also establish a new standard of crystallographic training, closer to nowadays industrial needs. Finally, NanED will favor the dissemination of 3D ED in academic and industrial laboratories, pushing Europe to be the leader for nanomaterial characterisation and development, with a noticeable and global economic impact. A3EDPI - Applicability of 3D Electron Diffraction in the Pharmaceutical Industry Research Project | 3 Project MembersNo Description available A programmable e-beam shaper for diffractive imaging of biological structures at Å resolution Research Project | 2 Project MembersNo Description available Hybrid pixel detectors for electron diffraction of nano-samples Research Project | 5 Project MembersWe propose adapting the Eiger hybrid pixel detector developed at PSI and commercialised by the awardwinning Swiss company Dectris for measuring the atomic structure of nanometer sized samples by free electron diffraction. Our pilot electron diffraction studies with CERN-developed Timepix hybrid pixel detectors with an Si sensor, indicate that Eiger detectors with a CdTe or GaAs sensor would ensure a major improvement in performance. Currently, Eiger detectors also have an Si sensor, like Medipix. The improvements we propose will allow us to study 3D structures of molecules in atomic detail using only minute amounts of sample, including crystals of organic compounds that are only 20 nm in size. This will be a significant step forwards in mastering the molecular world at the sub-nanometer scale. We will build an Eiger detector into a 300 kV electron microscope, and quantify its parameters for highenergy electron detection (DQE as a function of resolution and dose). We will investigate how to optimally combine the Eiger design with a high Z sensor (GaAs or CdTe). We will validate our results in structural studies of weakly diffracting, radiation sensitive nano-samples (pharmaceuticals, protein nano-crystals, zeolites and other nano-particles), which currently can only be studied in bulk. We will test to what extent the detector can be used for imaging of radiation sensitive samples using geometric superresolution. Our project will result in a scientific instrument that can be developed by Dectris into a commercial product. 1 1
Biomolecules in motion: Electron diffraction studies of native protein samples in graphene liquid cells. Research Project | 1 Project MembersNo Description available
Single molecule electron diffraction Research Project | 4 Project MembersI propose establishing a technology platform for validating single molecule electron diffraction (simED) as an alternative, general method for structural studies of dynamic biomolecular complexes at atomic resolution. There is significant evidence that simED could boost the low signal-to-noise ratio of cryo-EM single particle analysis by an order of magnitude or more, potentially allowing structural studies beyond current capabilities and extending resolution in ongoing projects. The proposal plans developing simED by implementing unique instrumentation, automated data collection protocols and exploring phasing methods from protein crystallography. This development of hardware, software and automated data collection protocols also strongly supports nano-crystallographic applications, including pre-screening of nanocrystals for SwissFEL, polymorph screening in pharmaceutical research and further development of protein nanocrystallography within the EU-funded innovative training network "NaNED" (https://cordis.europa.eu/project/id/956099) kicking off in 2021. The proposal links the development of an advanced technology platform to the elucidation of important, fundamental process of life. Linking these goals ensures that the development of simED addresses real needs in biological research. The proposal builds upon the results of my previous SNF project grant, that focused on developing electron diffraction of crystalline samples for structural biology. In the last few years, electron crystallography became an established method for atomic structure determination. In September 2020, Basel University purchased an electron microscope for developing simED technology (delivery: spring 2021), that will initially be located at the PSI. It will be enhanced with a commercial post-column energy filter and a PSI JUNGFRAU direct electron detector. The new equipment is funded jointly by Basel University and the PSI and fully dedicated to electron diffraction studies, including the development of simED. It falls under responsibility of my joint research group located at these two institutions. If simED cannot produce data of the required quality, we will implement and further investigate cryo-electron ptychography using defocused convergent beam diffraction. This novel application in cryo-EM was published in June 2020 (Zhou, L et al. "Low-dose phase retrieval of biological specimens using cryo-electron ptychography". Nat Commun 11, 2773 (2020)). Like in simED, this method scans the sample with a narrow beam, but this beam is convergent, and the diffraction data are measured as highly defocused images, whereas in simED the beam is essentially parallel, and the data are measured in the far field. The simED infrastructure can support both methods optimally. Following ideas developed at the LMB by Russo and colleagues, we will also explore simED at lower electron energies, as this may further boost the signal-to-noise ration by reducing radiation damage by up to 25%. As a second backup, we will consider implementing single particle cryo-EM imaging at lower energy on our simED instrumentation. Sample optimization, theory, algorithms and software concepts developed in the course of this project may contribute to extending the resolution of single molecule XFEL X-ray diffraction beyond its current limits of approximately 100 nm.
NanED / Electron Nanocrystallography Research Project | 1 Project MembersThe atomic structure determination of inorganic, organic and macromolecular compounds is a hard challenge anytime the crystal size falls below the micron range, becoming no more suitable for single-crystal x-ray diffraction. Still, a number of chemicals with valuable commercial and medical implications can be synthesized only as nanocrystals or show phase/ polymorphic transitions during crystal growth. The development of more efficient tools able to disclose the nature of nanocrystalline materials is therefore a hot and transversal topic that links materials science, physics of diffraction, new instrument engineering, chemical production and pharmacology. Electron diffraction (ED) allows extracting structure information from single nanometric crystals. ED experienced a tremendous boost after the development of 3D routines for data collection, up to be enlisted among the main breakthroughs in Science. However, the development of 3D ED is still limited to few laboratories and is slowed by the lack of dedicated instrumentation. NanED aims to form a new generation of electron crystallographers, able to master and develop 3D ED techniques in an interdisciplinary and interconnected network, where competences and know-how of usually distant scientific sectors are shared and merged. NanED will gather all European scientists hitherto active in 3D ED development and a pool of large and small companies interested in instrument development and material or pharmaceutical production. NanED will deliver portable procedures for sample preparation, data collection and data analysis, suitable for the successful application of 3D ED to all kinds of compounds. NanED will also establish a new standard of crystallographic training, closer to nowadays industrial needs. Finally, NanED will favor the dissemination of 3D ED in academic and industrial laboratories, pushing Europe to be the leader for nanomaterial characterisation and development, with a noticeable and global economic impact.
A3EDPI - Applicability of 3D Electron Diffraction in the Pharmaceutical Industry Research Project | 3 Project MembersNo Description available
A programmable e-beam shaper for diffractive imaging of biological structures at Å resolution Research Project | 2 Project MembersNo Description available
Hybrid pixel detectors for electron diffraction of nano-samples Research Project | 5 Project MembersWe propose adapting the Eiger hybrid pixel detector developed at PSI and commercialised by the awardwinning Swiss company Dectris for measuring the atomic structure of nanometer sized samples by free electron diffraction. Our pilot electron diffraction studies with CERN-developed Timepix hybrid pixel detectors with an Si sensor, indicate that Eiger detectors with a CdTe or GaAs sensor would ensure a major improvement in performance. Currently, Eiger detectors also have an Si sensor, like Medipix. The improvements we propose will allow us to study 3D structures of molecules in atomic detail using only minute amounts of sample, including crystals of organic compounds that are only 20 nm in size. This will be a significant step forwards in mastering the molecular world at the sub-nanometer scale. We will build an Eiger detector into a 300 kV electron microscope, and quantify its parameters for highenergy electron detection (DQE as a function of resolution and dose). We will investigate how to optimally combine the Eiger design with a high Z sensor (GaAs or CdTe). We will validate our results in structural studies of weakly diffracting, radiation sensitive nano-samples (pharmaceuticals, protein nano-crystals, zeolites and other nano-particles), which currently can only be studied in bulk. We will test to what extent the detector can be used for imaging of radiation sensitive samples using geometric superresolution. Our project will result in a scientific instrument that can be developed by Dectris into a commercial product.
