Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
Link to record
Permanent link

Direct link
Brodmerkel, Maxim N.ORCID iD iconorcid.org/0000-0003-0458-0623
Alternative names
Publications (9 of 9) Show all publications
Brodmerkel, M. N., De Santis, E., Uetrecht, C., Caleman, C. & Marklund, E. (2024). Collision induced unfolding and molecular dynamics simulations of norovirus capsid dimers reveal strain-specific stability profiles. Physical Chemistry, Chemical Physics - PCCP
Open this publication in new window or tab >>Collision induced unfolding and molecular dynamics simulations of norovirus capsid dimers reveal strain-specific stability profiles
Show others...
2024 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084Article in journal (Refereed) Published
Abstract [en]

Collision induced unfolding is method used with ion mobility mass spectrometry to examine protein structures and their stability. Such experiments yield information about higher order protein structures, yet are unable to provide details about the underlying processes. That information can however be provided using molecular dynamics simulations. Here, we investigate the collision induced unfolding of norovirus capsid dimers from the Norwalk and Kawasaki strains by employing molecular dynamics simulations over a range of temperatures, representing different levels of activation. The dimers have highly similar structures, but the activation reveals differences in the dynamics that arises in response to the activation.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2024
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-500271 (URN)10.1039/D3CP06344E (DOI)
Funder
Swedish Research Council, 2021-05988Swedish Research Council, 2020-04825Swedish Research Council, 2018-00740Swedish National Infrastructure for Computing (SNIC), 2022-22-854Swedish National Infrastructure for Computing (SNIC), 2022-22-925Swedish National Infrastructure for Computing (SNIC), 2022-22-947Swedish National Infrastructure for Computing (SNIC), 2022-5-415Swedish National Infrastructure for Computing (SNIC), 2022-23-57EU, Horizon 2020, 801406
Available from: 2023-04-13 Created: 2023-04-13 Last updated: 2024-04-11Bibliographically approved
Kierspel, T., Kadek, A., Barran, P., Bellina, B., Bijedic N, A., Brodmerkel, M. N., . . . Uetrecht, C. (2023). Coherent diffractive imaging of proteins and viral capsids: simulating MS SPIDOC. Analytical and Bioanalytical Chemistry, 415(18 SI), 4209-4220
Open this publication in new window or tab >>Coherent diffractive imaging of proteins and viral capsids: simulating MS SPIDOC
Show others...
2023 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 415, no 18 SI, p. 4209-4220Article in journal (Refereed) Published
Abstract [en]

MS SPIDOC is a novel sample delivery system designed for single (isolated) particle imaging at X-ray Free-Electron Lasers that is adaptable towards most large-scale facility beamlines. Biological samples can range from small proteins to MDa particles. Following nano-electrospray ionization, ionic samples can be m/z-filtered and structurally separated before being oriented at the interaction zone. Here, we present the simulation package developed alongside this prototype. The first part describes how the front-to-end ion trajectory simulations have been conducted. Highlighted is a quadrant lens; a simple but efficient device that steers the ion beam within the vicinity of the strong DC orientation field in the interaction zone to ensure spatial overlap with the X-rays. The second part focuses on protein orientation and discusses its potential with respect to diffractive imaging methods. Last, coherent diffractive imaging of prototypical T = 1 and T = 3 norovirus capsids is shown. We use realistic experimental parameters from the SPB/SFX instrument at the European XFEL to demonstrate that low-resolution diffractive imaging data (q < 0.3 nm−1) can be collected with only a few X-ray pulses. Such low-resolution data are sufficient to distinguish between both symmetries of the capsids, allowing to probe low abundant species in a beam if MS SPIDOC is used as sample delivery.

Place, publisher, year, edition, pages
Springer Nature, 2023
Keywords
SPI, X-ray, Native MS, Protein complex structure, Viral particles, Simulation, Modeling
National Category
Biophysics
Identifiers
urn:nbn:se:uu:diva-500359 (URN)10.1007/s00216-023-04658-y (DOI)000963181300001 ()37014373 (PubMedID)
Funder
Swedish Research Council, 2018-00740Swedish Research Council, 2020-04825EU, Horizon 2020, 801406
Available from: 2023-04-14 Created: 2023-04-14 Last updated: 2024-01-26Bibliographically approved
Brodmerkel, M. N., De Santis, E., Caleman, C. & Marklund, E. (2023). Rehydration Post-orientation: Investigating Field-Induced Structural Changes via Computational Rehydration. The Protein Journal, 42(3), 205-218
Open this publication in new window or tab >>Rehydration Post-orientation: Investigating Field-Induced Structural Changes via Computational Rehydration
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
Keywords
Molecular dynamics simulation, Protein hydration, Electric dipole, Protein structure, Structural biology, X-rays
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-499999 (URN)10.1007/s10930-023-10110-y (DOI)000966256600001 ()37031302 (PubMedID)
Funder
Swedish Research Council, 2020-04825Swedish Research Council, 2018-00740Swedish Research Council, 2021-05988EU, Horizon 2020, 801406
Available from: 2023-04-10 Created: 2023-04-10 Last updated: 2023-08-15Bibliographically approved
Brodmerkel, M. N. (2023). Theoretical and Biochemical: Advancing Protein Structure Investigations with Complementing Computations. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
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
Brodmerkel, M. N., De Santis, E., Uetrecht, C., Caleman, C. & Marklund, E. (2022). Stability and conformational memory of electrosprayed and rehydrated bacteriophage MS2 virus coat proteins. Current Research in Structural Biology, 4, 338-348
Open this publication in new window or tab >>Stability and conformational memory of electrosprayed and rehydrated bacteriophage MS2 virus coat proteins
Show others...
2022 (English)In: Current Research in Structural Biology, E-ISSN 2665-928X, Vol. 4, p. 338-348Article in journal (Refereed) Published
Abstract [en]

Proteins are innately dynamic, which is important for their functions, but which also poses significant challenges when studying their structures. Gas-phase techniques can utilise separation and a range of sample manipulations to transcend some of the limitations of conventional techniques for structural biology in crystalline or solution phase, and isolate different states for separate interrogation. However, the transfer from solution to the gas phase risks affecting the structures, and it is unclear to what extent different conformations remain distinct in the gas phase, and if resolution in silico can recover the native conformations and their differences. Here, we use extensive molecular dynamics simulations to study the two distinct conformations of dimeric capsid protein of the MS2 bacteriophage. The protein undergoes notable restructuring of its peripheral parts in the gas phase, but subsequent simulation in solvent largely recovers the native structure. Our results suggest that despite some structural loss due to the experimental conditions, gas-phase structural biology techniques provide meaningful data that inform not only about the structures but also conformational dynamics of proteins.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
Molecular dynamics simulations, Bacteriophage, Gas-phase structure, Protein structure, Solvation, Electrospray ionization
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-499621 (URN)10.1016/j.crstbi.2022.10.001 (DOI)36440379 (PubMedID)
Funder
Swedish Research Council, 2020-04825EU, Horizon 2020, 801406Swedish Research Council, 2021-05988
Available from: 2023-04-03 Created: 2023-04-03 Last updated: 2023-10-19Bibliographically approved
Duelfer, J., Yan, H., Brodmerkel, M. N., Creutznacher, R., Mallagaray, A., Peters, T., . . . Uetrecht, C. (2021). Glycan-Induced Protein Dynamics in Human Norovirus P Dimers Depend on Virus Strain and Deamidation Status. Molecules, 26(8), Article ID 2125.
Open this publication in new window or tab >>Glycan-Induced Protein Dynamics in Human Norovirus P Dimers Depend on Virus Strain and Deamidation Status
Show others...
2021 (English)In: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 26, no 8, article id 2125Article in journal (Refereed) Published
Abstract [en]

Noroviruses are the major cause of viral gastroenteritis and re-emerge worldwide every year, with GII.4 currently being the most frequent human genotype. The norovirus capsid protein VP1 is essential for host immune response. The P domain mediates cell attachment via histo blood-group antigens (HBGAs) in a strain-dependent manner but how these glycan-interactions actually relate to cell entry remains unclear. Here, hydrogen/deuterium exchange mass spectrometry (HDX-MS) is used to investigate glycan-induced protein dynamics in P dimers of different strains, which exhibit high structural similarity but different prevalence in humans. While the almost identical strains GII.4 Saga and GII.4 MI001 share glycan-induced dynamics, the dynamics differ in the emerging GII.17 Kawasaki 308 and rare GII.10 Vietnam 026 strain. The structural aspects of glycan binding to fully deamidated GII.4 P dimers have been investigated before. However, considering the high specificity and half-life of N373D under physiological conditions, large fractions of partially deamidated virions with potentially altered dynamics in their P domains are likely to occur. Therefore, we also examined glycan binding to partially deamidated GII.4 Saga and GII.4 MI001 P dimers. Such mixed species exhibit increased exposure to solvent in the P dimer upon glycan binding as opposed to pure wildtype. Furthermore, deamidated P dimers display increased flexibility and a monomeric subpopulation. Our results indicate that glycan binding induces strain-dependent structural dynamics, which are further altered by N373 deamidation, and hence hint at a complex role of deamidation in modulating glycan-mediated cell attachment in GII.4 strains.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
glycan interaction, norovirus capsid protein VP1, protruding domain, HDX-MS, native MS, hydrogen, deuterium exchange mass spectrometry
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-443208 (URN)10.3390/molecules26082125 (DOI)000644580400001 ()33917179 (PubMedID)
Funder
EU, Horizon 2020, 801406Swedish National Infrastructure for Computing (SNIC), 2019/4-554Swedish National Infrastructure for Computing (SNIC), 2020/5-100Swedish Research Council
Available from: 2021-05-25 Created: 2021-05-25 Last updated: 2024-01-15Bibliographically approved
Sinelnikova, A., Mandl, T., Östlin, C., Grånäs, O., Brodmerkel, M. N., Marklund, E. & Caleman, C. (2021). Reproducibility in the unfolding process of protein induced by an external electric field. Chemical Science, 12(6), 2030-2038
Open this publication in new window or tab >>Reproducibility in the unfolding process of protein induced by an external electric field
Show others...
2021 (English)In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 12, no 6, p. 2030-2038Article in journal (Refereed) Published
Abstract [en]

The dynamics of proteins are crucial for their function. However, commonly used techniques for studying protein structures are limited in monitoring time-resolved dynamics at high resolution. Combining electric fields with existing techniques to study gas phase proteins, such as Single Particle Imaging using Free-electron Lasers and gas phase Small Angle X-ray Scattering, has the potential to open up a new era in time-resolved studies of gas phase protein dynamics. Using molecular dynamics simulations, we identify well-defined unfolding pathways of a protein, induced by experimentally achievable external electric fields. Our simulations show that strong electric fields in conjunction with short pulsed X-ray sources such as Free-electron Lasers can be a new path for imaging dynamics of gas-phase proteins at high spatial and temporal resolution.

Place, publisher, year, edition, pages
Royal Society of ChemistryRoyal Society of Chemistry (RSC), 2021
National Category
Biophysics Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-429912 (URN)10.1039/D0SC06008A (DOI)000619216100039 ()
Funder
EU, Horizon 2020, 801406Swedish Research Council, 2018-00740
Available from: 2021-01-06 Created: 2021-01-06 Last updated: 2024-01-15Bibliographically approved
Mandl, T., Östlin, C., Dawod, I. E., Brodmerkel, M. N., Marklund, E., Martin, A. V., . . . Caleman, C. (2020). Structural Heterogeneity in Single Particle Imaging Using X-ray Lasers. Journal of Physical Chemistry Letters, 11(15), 6077-6083
Open this publication in new window or tab >>Structural Heterogeneity in Single Particle Imaging Using X-ray Lasers
Show others...
2020 (English)In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 11, no 15, p. 6077-6083Article in journal (Refereed) Published
Abstract [en]

One of the challenges facing single particle imaging with ultrafast X-ray pulses is the structural heterogeneity of the sample to be imaged. For the method to succeed with weakly scattering samples, the diffracted images from a large number of individual proteins need to be averaged. The more the individual proteins differ in structure, the lower the achievable resolution in the final reconstructed image. We use molecular dynamics to simulate two globular proteins in vacuum, fully desolvated as well as with two different solvation layers, at various temperatures. We calculate the diffraction patterns based on the simulations and evaluate the noise in the averaged patterns arising from the structural differences and the surrounding water. Our simulations show that the presence of a minimal water coverage with an average 3 Å thickness will stabilize the protein, reducing the noise associated with structural heterogeneity, whereas additional water will generate more background noise.

National Category
Biophysics Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:uu:diva-416668 (URN)10.1021/acs.jpclett.0c01144 (DOI)000562064500038 ()32578996 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC 2019/8-30EU, Horizon 2020, 801406Swedish Research Council, 201800740Australian Research Council, DP190103027
Available from: 2020-07-28 Created: 2020-07-28 Last updated: 2024-01-09Bibliographically approved
Brodmerkel, M., De Santis, E., Konijnenberg, A., Sobott, F. & Marklund, E. G.Molecular dynamics simulations reveal barrel opening during the unfolding of the outer membrane protein FhaC.
Open this publication in new window or tab >>Molecular dynamics simulations reveal barrel opening during the unfolding of the outer membrane protein FhaC
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Many membrane proteins carry out gatekeeping and transport functions across the membrane, which makes them tremendously important for the control of what passes into or out from the cell. Their underlying dynamics can be very challenging to capture for structural biology techniques, for which structural heterogeneity often is problematic. Native ion mobility mass spectrometry (IM-MS) is capable of maintaining non-covalent interactions between biomolecules in vacuo, allowing for intact protein complexes from heterogeneous mixtures to be analysed with respect to their masses and structures, making it a powerful tool for structural biology. Recent collision induced unfolding (CIU) experiments, where IM-MS is used to track the unfolding of proteins after activation, were used to investigate the dynamics of the membrane protein FhaC from Bordetella pertussis. FhaC is a β-barrel transmembrane protein found in the outer membrane, where it secretes virulence factors to the outside of the bacterium, requiring notable changes to its structure. CIU cannot on its own provide detailed information about the structural changes along the unfolding pathway. Here, we use MD simulations to mimic the CIU experiments to see if the unfolding proceeds as expected, with cytoplasm-facing domains leading the unfolding, or if other parts of the structure breaks first. By separating our simulation data according to experimental CIU data from literature, we match the structures in the former to the unfolding states identified in the latter, and find that FhaC instead unfolds from a “seam” in the β-barrel. In a wider context, our investigation provides insights into the structural stability and unfolding dynamics of β-barrel membrane proteins and how they can be studied using a combination of CIU and MD.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-500273 (URN)
Available from: 2023-04-13 Created: 2023-04-13 Last updated: 2023-04-25Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0458-0623

Search in DiVA

Show all publications