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Proteins, Lipids, and Water in the Gas Phase
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.ORCID iD: 0000-0002-9804-5009
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
2011 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 11, no 1, 50-59 p.Article in journal (Refereed) Published
Abstract [en]

Evidence from mass-spectrometry experiments and molecular dynamics simulations suggests that it is possible to transfer proteins, or in general biomolecular aggregates, from solution to the gas-phase without grave impact on the structure. If correct, this allows interpretation of such experiments as a probe of physiological behavior. Here, we survey recent experimental results from mass spectrometry and ion-mobility spectroscopy and combine this with observations based on molecular dynamics simulation, in order to give a comprehensive overview of the state of the art in gas-phase studies. We introduce a new concept in protein structure analysis by determining the fraction of the theoretical possible numbers of hydrogen bonds that are formed in solution and in the gas-phase. In solution on average 43% of the hydrogen bonds is realized, while in vacuo this fraction increases to 56%. The hydrogen bonds stabilizing the secondary structure (alpha-helices, beta-sheets) are maintained to a large degree, with additional hydrogen bonds occurring when side chains make new hydrogen bonds to rest of the protein rather than to solvent. This indicates that proteins that are transported to the gas phase in a native-like manner in many cases will be kinetically trapped in near-physiological structures. Simulation results for lipid-and detergent-aggregates and lipid-coated (membrane) proteins in the gas phase are discussed, which in general point to the conclusion that encapsulating proteins in "something'' aids in the conservation of native-like structure. Isolated solvated micelles of cetyl-tetraammonium bromide quickly turn into reverse micelles whereas dodecyl phosphocholine micelles undergo much slower conversions, and do not quite reach a reverse micelle conformation within 100 ns.

Place, publisher, year, edition, pages
2011. Vol. 11, no 1, 50-59 p.
Keyword [en]
GROMACS, insulin, lysozyme, myoglobin, OmpA, structures, Trp-Cage, ubiquitin, X-ray
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-145221DOI: 10.1002/mabi.201000291ISI: 000285932600006PubMedID: 21136535OAI: oai:DiVA.org:uu-145221DiVA: diva2:395762
Available from: 2011-02-08 Created: 2011-02-07 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Gas-Phase Protein Structure Under the Computational Microscope: Hydration, Titration, and Temperature
Open this publication in new window or tab >>Gas-Phase Protein Structure Under the Computational Microscope: Hydration, Titration, and Temperature
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Although the native environment of the vast majority of proteins is a complex aqueous solution, like the interior of a cell, many analysis methods for assessing chemical and physical properties of biomolecules require the sample to be aerosolized; that is, transferred to the gas-phase. An important example is electrospray-ionization mass spectrometry, which can provide a wide range of information about e.g. biomolecules. That includes structural features, charged sites, and gas-phase equilibrium constants of reactions. To date much of the microscopic detail about the aerosolization process remains beyond the limits of experimental observation. How is the gas-phase structure of a protein related to the solution-phase structure? How transferable are observations done in the gas phase to solution? On the basis of classical molecular-dynamics simulations this thesis reveals important features of gas-phase biomolecular structure near the end of the the aerosolization process, the relation between gas-phase structure and native structure, microscopic detail about the de-wetting of gas-phase biomolecules, and the impact of temperature and residual solvent on structure preservation. Residual solvent on proteins is shown to have a stabilizing effect on proteins, in part because it allows the scarcely hydrated protein to cool through solvent evaporation, but also because part of the solvent provides structural support by hydrogen bonding to the protein. The gas-phase structure of micellar aggregates is seen to depend on composition, where some types of lipids cause rapid micelle inversion, whereas others maintain much of their collective structure when transferred to the gas phase. The thesis also addresses proton-transfer reactions, which have an impact on the biophysical aspects of proteins, both in the gas phase and in solution. The thesis presents a computationally efficient method for including proton-transfer reactions in classical molecular-dynamics simulations, which expands the range of scientific problems that can be addressed with molecular dynamics.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 826
Keyword
Molecular dynamics, gas phase, proteins, micelles, proton transfer, Grothuss mechanism, kinetics
National Category
Physical Sciences
Research subject
Physics with specialization in Biophysics
Identifiers
urn:nbn:se:uu:diva-151006 (URN)978-91-554-8080-6 (ISBN)
Public defence
2011-05-25, BMC B22, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2011-05-04 Created: 2011-04-10 Last updated: 2011-07-01Bibliographically approved
2. Exploring the Molecular Dynamics of Proteins and Viruses
Open this publication in new window or tab >>Exploring the Molecular Dynamics of Proteins and Viruses
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Knowledge about structure and dynamics of the important biological macromolecules — proteins, nucleic acids, lipids and sugars — helps to understand their function. Atomic-resolution structures of macromolecules are routinely captured with X-ray crystallography and other techniques. In this thesis, simulations are used to explore the dynamics of the molecules beyond the static structures.

Viruses are machines constructed from macromolecules. Crystal structures of them reveal little to no information about their genomes. In simulations of empty capsids, we observed a correlation between the spatial distribution of chloride ions in the solution and the position of RNA in crystals of satellite tobacco necrosis virus (STNV) and satellite tobacco mosaic virus (STMV). In this manner, structural features of the non-symmetric RNA could also be inferred.

The capsid of STNV binds calcium ions on the icosahedral symmetry axes. The release of these ions controls the activation of the virus particle upon infection. Our simulations reproduced the swelling of the capsid upon removal of the ions and we quantified the water permeability of the capsid. The structure and dynamics of the expanded capsid suggest that the disassembly is initiated at the 3-fold symmetry axis.

Several experimental methods require biomolecular samples to be injected into vacuum, such as mass-spectrometry and diffractive imaging of single particles. It is therefore important to understand how proteins and molecule-complexes respond to being aerosolized. In simulations we mimicked the dehydration process upon going from solution into the gas phase. We find that two important factors for structural stability of proteins are the temperature and the level of residual hydration. The simulations support experimental claims that membrane proteins can be protected by a lipid micelle and that a non-membrane protein could be stabilized in a reverse micelle in the gas phase. A water-layer around virus particles would impede the signal in diffractive experiments, but our calculations estimate that it should be possible to determine the orientation of the particle in individual images, which is a prerequisite for three-dimensional reconstruction.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 45 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 919
Keyword
molecular dynamics, virus dynamics, capsid dissolution, satellite tobacco necrosis virus, satellite tobacco mosaic virus, virus genome structure, gas phase protein structure, water layer, micelle embedded protein, membrane protein
National Category
Biological Sciences Biochemistry and Molecular Biology Biophysics Structural Biology
Research subject
Chemistry with specialization in Biophysics
Identifiers
urn:nbn:se:uu:diva-172284 (URN)978-91-554-8335-7 (ISBN)
Public defence
2012-05-25, B41, Uppsala Biomedicinska Centrum, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Note
BMC B41, 25/5, 9:15Available from: 2012-05-04 Created: 2012-04-03 Last updated: 2012-08-01Bibliographically approved

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van der Spoel, DavidLarsson, Daniel S. D.Caleman, Carl

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