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      Top or Middle? Up or Down? Toward a Standard Lexicon for Protein Top-Down and Allied Mass Spectrometry Approaches

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          Abstract

          In recent years, there has been increasing interest in top-down mass spectrometry (TDMS) approaches for protein analysis, driven both by technological advancements and efforts such as those by the multinational Consortium for Top-Down Proteomics (CTDP). Today, diverse sample preparation and ionization methods are employed to facilitate TDMS analysis of denatured and native proteins and their complexes. The goals of these studies vary, ranging from protein and proteoform identification, to determination of the binding site of a (non)covalently-bound ligand, and in some cases even with the aim to study the higher order structure of proteins and complexes. Currently, however, no widely accepted terminology exists to precisely and unambiguously distinguish between the different types of TDMS experiments that can be performed. Instead, ad hoc developed terminology is often used, which potentially complicates communication of top-down and allied methods and their results. In this communication, we consider the different types of top-down (or top-down-related) MS experiments that have been performed and reported, and define distinct categories based on the protocol used and type(s) of information that can be obtained. We also consider the different possible conventions for distinguishing between middle- and top-down MS, based on both sample preparation and precursor ion mass. We believe that the proposed framework presented here will prove helpful for researchers to communicate about TDMS and will be an important step toward harmonizing and standardizing this growing field.

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          Most cited references 74

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          Proteoform: a single term describing protein complexity.

           Ryan Smith,  Neil Kelleher,   (2013)
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            Determination of monoisotopic masses and ion populations for large biomolecules from resolved isotopic distributions.

            The coupling of electrospray ionization with Fourier-transform mass spectrometry allows the analysis of large biomolecules with mass-measuring errors of less than 1 ppm. The large number of atoms incorporated in these molecules results in a low probability for the all-monoisotopic species. This produces the potential to misassign the number of heavy isotopes in a specific peak and make a mass error of ±1 Da, although the certainty of the measurement beyond the decimal place is greater than 0.1 Da. Statistical tests are used to compare the measured isotopic distribution with the distribution for a model molecule of the same average molecular mass, which allows the assignment of the monoisotopic mass, even in cases where the monoisotopic peak is absent from the spectrum. The statistical test produces error levels that are inversely proportional to the number of molecules in a distribution, which allows an estimation of the number of ions in the trapped ion cell. It has been determined, via this method that 128 charges are required to produce a signal-to-noise ratio of 3:1, which correlates well with previous experimental methods.
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              Native ion mobility-mass spectrometry and related methods in structural biology.

              Mass spectrometry-based methods have become increasingly important in structural biology - in particular for large and dynamic, even heterogeneous assemblies of biomolecules. Native electrospray ionization coupled to ion mobility-mass spectrometry provides access to stoichiometry, size and architecture of noncovalent assemblies; while non-native approaches such as covalent labeling and H/D exchange can highlight dynamic details of protein structures and capture intermediate states. In this overview article we will describe these methods and highlight some recent applications for proteins and protein complexes, with particular emphasis on native MS analysis. This article is part of a Special Issue entitled: Mass spectrometry in structural biology. Copyright © 2012 Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                f.lermyte@warwick.ac.uk
                Journal
                J Am Soc Mass Spectrom
                J. Am. Soc. Mass Spectrom
                Journal of the American Society for Mass Spectrometry
                Springer US (New York )
                1044-0305
                1879-1123
                9 May 2019
                9 May 2019
                2019
                : 30
                : 7
                : 1149-1157
                Affiliations
                [1 ]ISNI 0000 0000 8809 1613, GRID grid.7372.1, School of Engineering, , University of Warwick, ; Coventry, CV4 7AL UK
                [2 ]ISNI 0000 0000 8809 1613, GRID grid.7372.1, Department of Chemistry, , University of Warwick, ; Coventry, CV4 7AL UK
                [3 ]ISNI 0000000121839049, GRID grid.5333.6, Spectroswiss, , EPFL Innovation Park, ; 1015 Lausanne, Switzerland
                [4 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Chemistry and Biochemistry, Department of Biological Chemistry, David Geffen School of Medicine, and UCLA/DOE Institute of Genomics and Proteomics, , University of California, ; Los Angeles, CA USA
                Article
                2201
                10.1007/s13361-019-02201-x
                6591204
                31073892
                © The Author(s) 2019

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000266, Engineering and Physical Sciences Research Council;
                Award ID: EP/N033191/1
                Award ID: EP/N033191/1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01GM103479
                Award Recipient :
                Categories
                Critical Insight
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                © American Society for Mass Spectrometry 2019

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