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Technology Advance and Application of Cryo-Electron Microscopy in Molecular Biology and Biomedicine

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (15 May 2024) | Viewed by 6251

Special Issue Editors


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Guest Editor
School of Physics, National Biomedical Imaging Center, Peking-Tsinghua Joint Center for Life Sciences & Center for Quantitative Biology, Peking University, Beijing 100871, China
Interests: biophysics; chemical biology; molecular biology; cryo-electron microscopy

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Guest Editor
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
Interests: cryo-EM/cryo-ET; image analysis and statistics; methods development; simulations; AI/ML; molecular and cellular biology; virology; neuroscience

Special Issue Information

Dear Colleagues,

The resolution revolution and widespread applications of cryo-electron microscopy (cryo-EM) in the past decade have virtually changed all aspects of molecular biology and biomedical research. The present field of cryo-EM approaches and applications is a highly vibrant, multidisciplinary global community that draws talented researchers from all traditional disciplines, including those from mathematics, physics, chemistry and computer sciences, who have collectively changed the landscape of how cryo-EM can be used to address significant, hitherto intractable, problems and challenges in molecular biology, biochemistry and biomedicine. Many structures of large, dynamic complex machineries of essential cellular functions in thermodynamically stable states which are refractory to other structural determination technologies have been determined at high resolution by cryo-EM. It has now also become possible to visualize functional kinetics and non-equilibrium conformational dynamics at near-atomic resolution with the state-of-the-art methodology enabled by time-resolved cryo-EM. These advances open tremendous opportunities at the forefront of research in molecular biology and biomedicine.

This Special Issue will focus on all aspects of technological advancement and the application of cryo-EM, including in situ cryo-electron tomography (cryo-ET), in molecular biology and biomedicine. We particularly welcome high-quality original studies with respect to experimental methods for cryo-EM/ET sample preparation and imaging, including cryoFIB-SEM, cryo-CLEM, and related methodologies. We also welcome computational and machine-learning tools, including simulations, for analyzing heterogeneous cryo-EM/ET data, cryo-EM/ET analysis of structural dynamics of important molecular machines using novel strategies and approaches, and particularly the application and development of cryo-EM/ET to structure-based drug discovery and pharmacological applications, as well as the integration or hybridization of cryo-EM/ET with complementary approaches.

Both high-quality original research articles and cutting-edge focused reviews summarizing important advances in the field are welcome for submission. Authors are encouraged to take advantage of the great flexibility of the article format with unlimited length, and to use this Special Issue as a permanent digital forum to document their unique scholarly opinions and novel concepts, while enjoying the great visibility of this open-access online journal that is indexed in major citation databases such as SCIE, PubMed, Scopus and Crossref. All submissions will undergo rigorous and timely peer review prior to acceptance. Poor quality or out-of-scope submission will be rejected without sending out for peer review. This Special Issue aims to publish up to 10 peer-reviewed full-length articles, but exceptions will be considered for high-quality original articles.

Prof. Dr. Youdong Mao
Dr. Jesús Gerardo Galaz-Montoya
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cryo-electron microscopy (cryo-EM) 
  • cryo-electron tomography (cryo-ET) 
  • cryo-EM sample preparation 
  • single-particle analysis 
  • sub-tomogram averaging 
  • structural determination 
  • molecular machines 
  • structural dynamics 
  • structure-based drug discovery 
  • machine learning 
  • conformational states 
  • conformational landscape 
  • conformational continuum 
  • time-resolved cryo-EM 
  • atomic modeling

Published Papers (2 papers)

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Research

16 pages, 2620 KiB  
Article
Full-Length Model of SaCas9-sgRNA-DNA Complex in Cleavage State
by Wenhao Du, Haixia Zhu, Jiaqiang Qian, Dongmei Xue, Sen Zheng and Qiang Huang
Int. J. Mol. Sci. 2023, 24(2), 1204; https://doi.org/10.3390/ijms24021204 - 7 Jan 2023
Viewed by 1941
Abstract
Staphylococcus aureus Cas9 (SaCas9) is a widely used genome editing tool. Understanding its molecular mechanisms of DNA cleavage could effectively guide the engineering optimization of this system. Here, we determined the first cryo-electron microscopy structure of the SaCas9-sgRNA-DNA ternary complex. This structure reveals [...] Read more.
Staphylococcus aureus Cas9 (SaCas9) is a widely used genome editing tool. Understanding its molecular mechanisms of DNA cleavage could effectively guide the engineering optimization of this system. Here, we determined the first cryo-electron microscopy structure of the SaCas9-sgRNA-DNA ternary complex. This structure reveals that the HNH nuclease domain is tightly bound to the cleavage site of the target DNA strand, and is in close contact with the WED and REC domains. Moreover, it captures the complete structure of the sgRNA, including the previously unresolved stem-loop 2. Based on this structure, we build a full-length model for the ternary complex in cleavage state. This model enables identification of the residues for the interactions between the HNH domain and the WED and REC domains. Moreover, we found that the stem-loop 2 of the sgRNA tightly binds to the PI and RuvC domains and may also regulate the position shift of the RuvC domain. Further mutagenesis and molecular dynamics simulations supported the idea that the interactions of the HNH domain with the WED and REC domains play an important role in the DNA cleavage. Thus, this study provides new mechanistic insights into the DNA cleavage of SaCas9 and is also useful for guiding the future engineering of SaCas9-mediated gene editing systems. Full article
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38 pages, 7181 KiB  
Article
Visualizing Conformational Space of Functional Biomolecular Complexes by Deep Manifold Learning
by Zhaolong Wu, Enbo Chen, Shuwen Zhang, Yinping Ma and Youdong Mao
Int. J. Mol. Sci. 2022, 23(16), 8872; https://doi.org/10.3390/ijms23168872 - 9 Aug 2022
Cited by 6 | Viewed by 3648
Abstract
The cellular functions are executed by biological macromolecular complexes in nonequilibrium dynamic processes, which exhibit a vast diversity of conformational states. Solving the conformational continuum of important biomolecular complexes at the atomic level is essential to understanding their functional mechanisms and guiding structure-based [...] Read more.
The cellular functions are executed by biological macromolecular complexes in nonequilibrium dynamic processes, which exhibit a vast diversity of conformational states. Solving the conformational continuum of important biomolecular complexes at the atomic level is essential to understanding their functional mechanisms and guiding structure-based drug discovery. Here, we introduce a deep manifold learning framework, named AlphaCryo4D, which enables atomic-level cryogenic electron microscopy (cryo-EM) reconstructions that approximately visualize the conformational space of biomolecular complexes of interest. AlphaCryo4D integrates 3D deep residual learning with manifold embedding of pseudo-energy landscapes, which simultaneously improves 3D classification accuracy and reconstruction resolution via an energy-based particle-voting algorithm. In blind assessments using simulated heterogeneous datasets, AlphaCryo4D achieved 3D classification accuracy three times those of alternative methods and reconstructed continuous conformational changes of a 130-kDa protein at sub-3 Å resolution. By applying this approach to analyze several experimental datasets of the proteasome, ribosome and spliceosome, we demonstrate its potential generality in exploring hidden conformational space or transient states of macromolecular complexes that remain hitherto invisible. Integration of this approach with time-resolved cryo-EM further allows visualization of conformational continuum in a nonequilibrium regime at the atomic level, thus potentially enabling therapeutic discovery against highly dynamic biomolecular targets. Full article
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