Hardware Software Synergy in Proteomics: Systematic Evaluation Across Mass Spectrometry Platforms, Search Engines, and Rescoring Methods
Abstract
Mass spectrometry-based proteomics has advanced through parallel improvements in hardware (instrumentation) and software (data analysis), yet whether these improvements interact synergistically or provide diminishing returns remains unclear. Here, we systematically evaluate hardware-software co-evolution across eight mass spectrometry platforms, three generations of search engines, and multiple rescoring approaches, yielding 72 unique hardware–software combinations spanning from 2004–2024. Our results reveal that hardware and software improvements produce synergistic rather than substitutive benefits. Here, machine learning-based rescoring consistently identifies peptides from low-intensity precursors that produce noisier, more challenging spectra. Crucially, because of increased sensitivity and speed, modern instruments detect more low-intensity precursors, increasing the population of challenging spectra where rescoring provides the greatest benefit. However, this expanded detection depth comes at a cost: recovered low-abundance peptides exhibit inherently higher quantification error, creating a fundamental trade-off between proteome coverage and quantification accuracy. Together, these findings provide a systematic overview of how hardware and software advances have jointly shaped proteomics performance over the past two decades.
Authors 13
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Ghent University · VIB-UGent Center for Medical Biotechnology
Affiliation as printed
Faculty of Medicine and Health Sciences
Ghent University
VIB
VIB-UGent Center for Medical Biotechnology
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Ghent University · VIB-UGent Center for Medical Biotechnology
Affiliation as printed
Faculty of Medicine and Health Sciences
Ghent University
VIB
VIB-UGent Center for Medical Biotechnology
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Ghent University · VIB-UGent Center for Medical Biotechnology
Affiliation as printed
Faculty of Medicine and Health Sciences
Ghent University
VIB
VIB-UGent Center for Medical Biotechnology
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Ghent University · VIB-UGent Center for Medical Biotechnology
Affiliation as printed
Faculty of Medicine and Health Sciences
Ghent University
VIB
VIB-UGent Center for Medical Biotechnology
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Magnus Palmblad Aachen
Leiden University Medical Center
Affiliation as printed
Center for Proteomics and Metabolomics
Leiden University Medical Center
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Affiliation as printed
Department of Computer Science
University of Antwerp
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The Netherlands Cancer Institute · Sanquin
Affiliation as printed
Department of Radiation Oncology
Netherlands Cancer Institute
Sanquin Research and Landsteiner Laboratory
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Technical University of Munich
Affiliation as printed
Computational Mass Spectrometry
Technical University of Munich
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Boston Children's Hospital · Northeastern University · Harvard University
Affiliation as printed
Boston Children's Hospital
Department of Pathology
Harvard Medical School
Institute for Experiential AI
Northeastern University
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Affiliation as printed
Bruker France SAS
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Centre National de la Recherche Scientifique · Proteomics French Infrastructure Core
Affiliation as printed
CNRS
Infrastructure Nationale de Protéomique ProFI − UAR 2048
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Centre National de la Recherche Scientifique · Ghent University · VIB-UGent Center for Medical Biotechnology · Proteomics French Infrastructure Core
Affiliation as printed
CNRS
Faculty of Medicine and Health Sciences
Ghent University
Infrastructure Nationale de Protéomique ProFI − UAR 2048
VIB
VIB-UGent Center for Medical Biotechnology
-
Ghent University · VIB-UGent Center for Medical Biotechnology
Affiliation as printed
Faculty of Medicine and Health Sciences
Ghent University
VIB
VIB-UGent Center for Medical Biotechnology
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