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Rehydration Post-orientation: Investigating Field-Induced Structural Changes via Computational Rehydration
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.ORCID iD: 0000-0003-0458-0623
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.ORCID iD: 0000-0001-5029-7429
Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607, Hamburg, Germany.ORCID iD: 0000-0003-2638-1940
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. (Erik Marklund)ORCID iD: 0000-0002-9804-5009
2023 (English)In: The Protein Journal, ISSN 1572-3887, E-ISSN 1875-8355, Vol. 42, no 3, p. 205-218Article in journal (Refereed) Published
Abstract [en]

Proteins can be oriented in the gas phase using strong electric fields, which brings advantages for structure determination using X-ray free electron lasers. Both the vacuum conditions and the electric-field exposure risk damaging the protein structures. Here, we employ molecular dynamics simulations to rehydrate and relax vacuum and electric-field exposed proteins in aqueous solution, which simulates a refinement of structure models derived from oriented gas-phase proteins. We find that the impact of the strong electric fields on the protein structures is of minor importance after rehydration, compared to that of vacuum exposure and ionization in electrospraying. The structures did not fully relax back to their native structure in solution on the simulated timescales of 200 ns, but they recover several features, including native-like intra-protein contacts, which suggests that the structures remain in a state from which the fully native structure is accessible. Our fndings imply that the electric fields used in native mass spectrometry are well below a destructive level, and suggest that structures inferred from X-ray difraction from gas-phase proteins are relevant for solution and in vivo conditions, at least after in silico rehydration.

Place, publisher, year, edition, pages
Springer Nature, 2023. Vol. 42, no 3, p. 205-218
Keywords [en]
Molecular dynamics simulation, Protein hydration, Electric dipole, Protein structure, Structural biology, X-rays
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-499999DOI: 10.1007/s10930-023-10110-yISI: 000966256600001PubMedID: 37031302OAI: oai:DiVA.org:uu-499999DiVA, id: diva2:1749573
Funder
Swedish Research Council, 2020-04825Swedish Research Council, 2018-00740Swedish Research Council, 2021-05988EU, Horizon 2020, 801406Available from: 2023-04-10 Created: 2023-04-10 Last updated: 2023-08-15Bibliographically approved
In thesis
1. Theoretical and Biochemical: Advancing Protein Structure Investigations with Complementing Computations
Open this publication in new window or tab >>Theoretical and Biochemical: Advancing Protein Structure Investigations with Complementing Computations
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Life as we know it today would not exist without proteins. The functions of proteins for us and other organisms are linked to their three-dimensional structures. As such, protein structure investigations are a crucial contribution for understanding proteins and the molecular basis of life. Some methods probe the structure of proteins in the gas phase, which brings various advantages as well as complications. Amongst them is mass spectrometry, a powerful method that provides a multitude of information on gaseous protein structures. Whilst mass spectrometry shines in obtaining data of the higher-order structures, atomistic details are out of reach. Molecular dynamics simulations on the other hand allow the interrogation of proteins in high-resolution, which makes it an ideal method for their structural research, be it in or out of solution.

This thesis aims to advance the understanding of protein structures and the methods for their study utilising classic molecular dynamics simulations. The research presented in this thesis can be divided into two themes, comprising the rehydration of vacuum-exposed structures and the interrogation of the induced unfolding process of proteins. Out of their native environment, proteins undergo structural changes when exposed to vacuum. Investigating the ability to revert those potential vacuum-induced structural changes by means of computational rehydration provided detailed information on the underlying protein dynamics and how much of the structure revert back to their solution norm. We have further shown through rehydration simulations that applying an external electric field for dipole-orientation purposes does not induce irreversible changes to the protein structures. Our investigations on the induced unfolding of protein structures allowed a detailed look into the process of unfolding, accurately pinpointing areas within the proteins that unfolded first. The details provided by our simulations enabled us to describe potential mechanisms of the unfolding processes of different proteins on an atomistic level. The obtained results thus provide a potent theoretical basis for current and future experiments, where it will be very interesting to see MD compared with or complemented to experiments.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2023. p. 96
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 2264
Keywords
Molecular dynamics simulation, Protein structure, Structural biology, Protein hydration, Electric dipole, Collision Induced Unfolding
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-500274 (URN)978-91-513-1797-7 (ISBN)
Public defence
2023-06-02, Room B41, Biomedicinska Centrum, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2023-05-11 Created: 2023-04-14 Last updated: 2023-05-11

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Brodmerkel, Maxim N.De Santis, EmilianoCaleman, CarlMarklund, Erik

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