History and Trends in Protein Sequencing
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High-resolution mass spectrometry platforms (Orbitrap Exploris, Fusion Lumos)
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Multi-dimensional protein quantification strategies (TMT, Label-Free, SILAC)
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PTM enrichment and targeted analysis modules
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Bioinformatics pipelines supporting AI-assisted peptide identification and protein annotation
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Integration with multi-omics studies, including transcriptomics, metabolomics, and chemical proteomics
The history of Protein Sequencing technology has marked the transition of modern life sciences from chemical reactions to system-level omics. From the pioneering Edman degradation method to today’s proteomics platforms centered around high-resolution mass spectrometry, the technological evolution of Protein Sequencing has continually expanded the depth, throughput, and functional analytical capacity of detection, laying a robust foundation for decoding the blueprint of life. This paper reviews the pivotal developmental milestones in Protein Sequencing and anticipates its future trajectories in cutting-edge fields such as functional omics, personalized medicine, and AI-assisted analysis.
Brief History of Development: Technological Evolution of Protein Sequencing
1. Edman Degradation Era (1950s-1980s)
The chemical sequencing method introduced by Pehr Edman, which sequentially cleaves the N-terminal amino acids and analyzes their structure, initiated research into the primary structure of proteins. Notable achievements include the complete sequencing of insulin. This method established the foundation of modern protein chemistry but was constrained by low throughput, lengthy processing times, and limitations on sequence length.
2. Rise of Mass Spectrometry (1990s-2000s)
The advent of soft ionization techniques such as electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) enabled the successful incorporation of large molecular proteins into mass spectrometry systems. Tandem mass spectrometry (MS/MS) subsequently facilitated the interpretation of peptide fragmentation spectra, establishing it as the mainstream approach in Protein Sequencing.
3. Era of Proteomics (2010s-present)
High-resolution mass spectrometry (such as the Orbitrap and time-of-flight systems), in combination with high-performance liquid chromatography (LC), has enabled high-throughput, multi-dimensional qualitative and quantitative analysis of the proteome. This era has seen the emergence of diverse quantification strategies, including label-free, TMT, and SILAC, while supporting the simultaneous identification of complex features such as post-translational modifications (PTMs), mutations, and splice isoforms.
Technical Advantages of Modern Protein Sequencing
1. Enables the detection of thousands of proteins and their modification sites, providing a comprehensive landscape of functional states.
2. Operates independently of genomic information, making it suitable for research on non-model organisms, antibody sequences, and natural products.
3. Achieves site-specific precision in identifying post-translational modifications (e.g., phosphorylation, acetylation, glycosylation).
4. Can be integrated with transcriptomics, metabolomics, and chemical proteomics to advance systems biology research.
Remaining Challenges
1. Detection of Low-Abundance Proteins Remains Challenging
Signal suppression, background interference, and a high dynamic range continue to limit the in-depth investigation of low-abundance functional proteins.
2. Precision in Modification Identification Is Constrained
The coexistence of multiple modification sites, complex fragmentation patterns, and incomplete databases hinder the accurate determination of modification sites.
3. The Burden of Data Interpretation Has Increased
The vast volume of mass spectrometry data necessitates the development of more efficient algorithms, bioinformatics platforms, and coordinated manual review.
Trends in Development: From Structural Recognition to Functional Insights
1. AI and Deep Learning Enhance Sequence Recognition
AlphaPept, Prosit, and similar AI-based tools accelerate the analysis of fragment spectra, enhancing the accuracy of peptide identification and the prediction of post-translational modifications.
2. Integration of In Situ Protein Sequencing with Single-Cell Technologies
Technologies such as spatial proteomics and single-cell mass spectrometry are advancing the spatial and high-resolution analysis of protein expression.
3. From Quantitative to Dynamic Functional Proteomics
By employing approaches including chemical probes, pulse-chase SILAC, and metabolic labeling, protein sequencing is extending to capture dynamic changes, activity states, and temporal dimensions of protein function.
MtoZ Biolabs Drives the Advancement of Cutting-Edge Protein Sequencing
MtoZ Biolabs is dedicated to establishing high-throughput, high-sensitivity, and customizable protein sequencing service platforms, offering:
We are committed to advancing protein sequencing from structural identification to dynamic functional interpretation, accelerating the translation of fundamental research into biomedical applications. From the pioneering Edman degradation method to today’s automated omics platforms driven by mass spectrometry and AI, protein sequencing technology continues to expand the frontiers of our understanding of biological systems. In the future, protein sequencing will sustain breakthroughs in areas such as personalized medicine, target discovery, and mechanism research. MtoZ Biolabs, leveraging its robust platform capabilities and expert support, will empower more researchers to use structural information as a guide to decode the true functional executors of life—proteins.
MtoZ Biolabs, an integrated chromatography and mass spectrometry (MS) services provider.
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