Mass spectrometry-based top-down proteomics has emerged as one of the most informative approaches in protein analysis because it provides the bird-eye view of all intact proteoforms generated from post-translational modifications and sequence variations. A major challenge in proteoform identification by database search is the combinatorial explosion of possible proteoforms resulting from combinations of sequence variations, post-translational modifications, and other molecular events, such as protein degradation. Here, we propose to a novel data model, called the mass graph, to efficiently represent a huge number of potential proteoforms, and design new mass graph-based alignment and filtering algorithms that precisely identify complex proteoforms at the proteome level. We will also develop a software pipeline that combines top-down mass spectrometry and RNA-Seq data to identify sample-specific proteoforms. The proposed research will be conducted by a group of researchers who have complementary expertise. All the proposed algorithms will be implemented as user-friendly open source software tools.
This project addresses the proteoform identification problem by top-down mass spectrometry and by top-down mass spectrometry-based proteogenomics. New data models and algorithms will be proposed for high-throughput proteome-wide identification of complex proteoforms with post-translational modifications and sequence variations. Software tools developed based on these algorithms will facilitate the decoding of complex proteoforms like histone proteins and the discovery of proteome biomarkers.
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|McCool, Elijah N; Lubeckyj, Rachele A; Shen, Xiaojing et al. (2018) Deep Top-Down Proteomics Using Capillary Zone Electrophoresis-Tandem Mass Spectrometry: Identification of 5700 Proteoforms from the Escherichia coli Proteome. Anal Chem 90:5529-5533|
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|Kou, Qiang; Wu, Si; Liu, Xiaowen (2018) Systematic Evaluation of Protein Sequence Filtering Algorithms for Proteoform Identification Using Top-Down Mass Spectrometry. Proteomics 18:|
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|Lubeckyj, Rachele A; McCool, Elijah N; Shen, Xiaojing et al. (2017) Single-Shot Top-Down Proteomics with Capillary Zone Electrophoresis-Electrospray Ionization-Tandem Mass Spectrometry for Identification of Nearly 600 Escherichia coli Proteoforms. Anal Chem 89:12059-12067|
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|Fornelli, Luca; Ayoub, Daniel; Aizikov, Konstantin et al. (2017) Top-down analysis of immunoglobulin G isotypes 1 and 2 with electron transfer dissociation on a high-field Orbitrap mass spectrometer. J Proteomics 159:67-76|
|Ma, Hongyan; Delafield, Daniel G; Wang, Zhe et al. (2017) Finding Biomass Degrading Enzymes Through an Activity-Correlated Quantitative Proteomics Platform (ACPP). J Am Soc Mass Spectrom 28:655-663|
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