CaltechAUTHORS
  A Caltech Library Service

The CryoEM Method MicroED as a Powerful Tool for Small Molecule Structure Determination

Jones, Christopher G. and Martynowycz, Michael W. and Hattne, Johan and Fulton, Tyler and Stoltz, Brian M. and Rodriguez, Jose A. and Nelson, Hosea M. and Gonen, Tamir (2018) The CryoEM Method MicroED as a Powerful Tool for Small Molecule Structure Determination. ACS Central Science, 4 (11). pp. 1587-1592. ISSN 2374-7943. PMCID PMC6276044. http://resolver.caltech.edu/CaltechAUTHORS:20181101-140146236

[img] PDF (ACS AuthorChoice) - Published Version
See Usage Policy.

4Mb
[img] PDF (ACS AuthorChoice) - In Press Version
See Usage Policy.

4Mb
[img] PDF - Submitted Version
Creative Commons Attribution Non-commercial No Derivatives.

7Mb
[img] Video (AVI) (Movie of continuous rotation MicroED data from a carbamazepine nanocrystal with corresponding resolution rings) - Supplemental Material
See Usage Policy.

3836Kb
[img] PDF (Procedures, chemical suppliers, and crystallographic data) - Supplemental Material
See Usage Policy.

2103Kb

Use this Persistent URL to link to this item: http://resolver.caltech.edu/CaltechAUTHORS:20181101-140146236

Abstract

In the many scientific endeavors that are driven by organic chemistry, unambiguous identification of small molecules is of paramount importance. Over the past 50 years, NMR and other powerful spectroscopic techniques have been developed to address this challenge. While almost all of these techniques rely on inference of connectivity, the unambiguous determination of a small molecule’s structure requires X-ray and/or neutron diffraction studies. In practice, however, X-ray crystallography is rarely applied in routine organic chemistry due to intrinsic limitations of both the analytes and the technique. Here we report the use of the electron cryo-microscopy (cryoEM) method microcrystal electron diffraction (MicroED) to provide routine and unambiguous structural determination of small organic molecules. From simple powders, with minimal sample preparation, we could collect high-quality MicroED data from nanocrystals (∼100 nm, ∼10^(–15) g) resulting in atomic resolution (<1 Å) crystal structures in minutes.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acscentsci.8b00760DOIArticle
https://pubs.acs.org/doi/suppl/10.1021/acscentsci.8b00760PublisherSupporting Information
https://chemrxiv.org/articles/The_CryoEM_Method_MicroED_as_a_Powerful_Tool_for_Small_Molecule_Structure_Determination/7215332OrganizationDiscussion Paper
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276044PubMed CentralArticle
ORCID:
AuthorORCID
Stoltz, Brian M.0000-0001-9837-1528
Nelson, Hosea M.0000-0002-4666-2793
Additional Information:© 2018 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: October 17, 2018; Published: November 2, 2018. Accession Codes: Data and materials availability: MicroED density maps have been deposited to the PDB (thiostrepton, 6MXF), EMDB (EMD-9282, EMD-9284, EMD-9285, EMD-9286, EMD-9287, EMD-9288, EMD-9289, EMD-9290, EMD-9291, EMD-9292), and CCDC (1876036, 1876037, 1876038, 1876039, 1876040, 1876041, 1876042, 1876043, 1876044, 1876045). Author Contributions: C.G.J. and M.W.M. contributed equally. C.G.J. performed experiments, developed the sample preparation techniques, refined structural data, prepared figures, and assisted with manuscript preparation. M.W.M performed experiments, developed the sample preparation techniques, collected data, refined structural data, prepared figures, and assisted with manuscript preparation. T.F. performed experiments. J.H. wrote the software for image conversion, participated in data analysis, refinement, and structure determination. J.A.R. performed experiments, developed the sample preparation techniques, and assisted with manuscript preparation. B.M.S. conceived of the project, designed experiments, and assisted with manuscript preparation. H.M.N. conceived of the project, designed experiments, performed experiments, developed the sample preparation techniques, and assisted with manuscript and figure preparation. T.G. performed experiments, collected data, developed the sample prep techniques, developed microscope data collection parameters, provided the microscope and expertise, and assisted in manuscript and figure preparation. C.G.J. would like to acknowledge the National Science Foundation for a predoctoral fellowship (DGE-1650604). B.M.S. acknowledges the NIH-NIGMS for generous funding (R01GM080269). J.A.R. is supported by DOE Grant DE-FC02-02ER63421, NIH-NIGMS Grant R35GM128867, and as a Beckman Young Investigator, a Searle Scholar, and a Pew Scholar. H.M.N. thanks The Packard Foundation, The Sloan Foundation, Pew Charitable Trusts, and the NIH-NIGMS (R35 GM128936) for generous funding. The Gonen laboratory is supported by funds from the Howard Hughes Medical Institute. The authors declare no competing financial interest. We thank Profesor Doug Rees (Caltech), Professor Bil Clemons (Caltech), and Dr. Michael Sawaya (UCLA) for useful discussions. We thank Byungkuk Yoo and Michael Takase (Caltech) for technical assistance with data analysis. We thank Beau Pritchett and Hendrik Klare for providing synthetic samples.
Funders:
Funding AgencyGrant Number
NSF Predoctoral FellowshipDGE-1650604
NIHR01GM080269
Department of Energy (DOE)DE-FC02-02ER63421
NIHR35GM128867
Caltech Beckman InstituteUNSPECIFIED
Searle Scholars ProgramUNSPECIFIED
Pew Charitable TrustUNSPECIFIED
David and Lucile Packard FoundationUNSPECIFIED
Alfred P. Sloan FoundationUNSPECIFIED
NIHR35 GM128936
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:MicroED; Small Molecules; Structure Determination; Organic Chemistry
PubMed Central ID:PMC6276044
Record Number:CaltechAUTHORS:20181101-140146236
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20181101-140146236
Official Citation:The CryoEM Method MicroED as a Powerful Tool for Small Molecule Structure Determination. Christopher G. Jones, Michael W. Martynowycz, Johan Hattne, Tyler J. Fulton, Brian M. Stoltz, Jose A. Rodriguez, Hosea M. Nelson, and Tamir Gonen. ACS Central Science 2018 4 (11), 1587-1592. DOI: 10.1021/acscentsci.8b00760
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90583
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:01 Nov 2018 21:20
Last Modified:17 Dec 2018 15:45

Repository Staff Only: item control page