Molecular simulation-based structural prediction of protein complexes in mass spectrometry: the human insulin dimer

Jinyu Li; Giulia Rossetti; Jens Dreyer; Simone Raugei; Emiliano Ippoliti; Bernhard Lüscher; Paolo Carloni

doi:10.1371/journal.pcbi.1003838

Molecular simulation-based structural prediction of protein complexes in mass spectrometry: the human insulin dimer

PLoS Comput Biol. 2014 Sep 11;10(9):e1003838. doi: 10.1371/journal.pcbi.1003838. eCollection 2014 Sep.

Authors

Jinyu Li¹, Giulia Rossetti², Jens Dreyer³, Simone Raugei⁴, Emiliano Ippoliti³, Bernhard Lüscher⁵, Paolo Carloni³

Affiliations

¹ Computational Biophysics, German Research School for Simulation Sciences (joint venture of RWTH Aachen University and Forschungszentrum Jülich, Germany), Jülich, Germany and Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, Jülich, Germany; Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
² Computational Biophysics, German Research School for Simulation Sciences (joint venture of RWTH Aachen University and Forschungszentrum Jülich, Germany), Jülich, Germany and Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, Jülich, Germany; Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich, Jülich, Germany.
³ Computational Biophysics, German Research School for Simulation Sciences (joint venture of RWTH Aachen University and Forschungszentrum Jülich, Germany), Jülich, Germany and Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, Jülich, Germany.
⁴ Fundamental and Computational Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, United States of America.
⁵ Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.

Abstract

Protein electrospray ionization (ESI) mass spectrometry (MS)-based techniques are widely used to provide insight into structural proteomics under the assumption that non-covalent protein complexes being transferred into the gas phase preserve basically the same intermolecular interactions as in solution. Here we investigate the applicability of this assumption by extending our previous structural prediction protocol for single proteins in ESI-MS to protein complexes. We apply our protocol to the human insulin dimer (hIns2) as a test case. Our calculations reproduce the main charge and the collision cross section (CCS) measured in ESI-MS experiments. Molecular dynamics simulations for 0.075 ms show that the complex maximizes intermolecular non-bonded interactions relative to the structure in water, without affecting the cross section. The overall gas-phase structure of hIns2 does exhibit differences with the one in aqueous solution, not inferable from a comparison with calculated CCS. Hence, care should be exerted when interpreting ESI-MS proteomics data based solely on NMR and/or X-ray structural information.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Insulin / chemistry*
Mass Spectrometry / methods*
Molecular Dynamics Simulation*
Protein Conformation
Proteomics / methods*
Thermodynamics

Substances

Insulin
insulin dimers

Grants and funding

Computing time granted by the John von Neumann Institute for Computing (NIC) with grant number HGR12. The URL of the funder: http://webarchiv.fz-juelich.de/nic/Allgemeines/Allgemeines-e.html The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.