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Simulations of Biomolecular Fragmentation and Diffraction with Ultrafast X-ray Lasers
Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.ORCID iD: 0000-0002-0021-4354
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Studies of biomolecules have recently seen substantial developments. New X-ray lasers allow for high-resolution imaging of protein crystals too small for conventional X-ray crystallography. Even structures of single particles have been determined at lower resolutions with these new sources. The secret lies in the ultrashort high-intensity pulses, which allow for diffraction and retrieval of structural information before the sample gets fragmented. However, the attainable resolution is still limited, in particular when imaging non-crystalline samples, making further advancements highly desired. In this thesis, some of the resolution-limiting obstacles facing single particle imaging (SPI) of proteins are studied in silico.

As the X-ray pulse interacts with injected single molecules, their spatial orientation is generally unknown. Recovering the orientation is essential to the structure determination process, and currently nontrivial. Molecular dynamics simulations show that the Coulomb explosion due to intense X-ray ionization could provide information pertaining to the original orientation. Used in conjunction with current methods, this would lead to an enhanced three-dimensional reconstruction of the protein.

Radiation damage and sample heterogeneity constitute considerable sources of noise in SPI. Pulse durations are presently not brief enough to circumvent damage, causing the sample to deteriorate during imaging, and the accuracy of the averaged diffraction pattern is impaired by structural variations. The extent of these effects were studied by molecular dynamics. Our findings suggest that radiation damage in terms of ionization and atomic displacement promotes a gating mechanism, benefiting imaging with longer pulses. Because of this, sample heterogeneity poses a greater challenge and efforts should be made to minimize its impact.

X-ray lasers generate pulses with a stochastic temporal distribution of photons, affecting the achievable resolution on a  pulse-to-pulse basis. Plasma simulations were performed to investigate how these fluctuations influence the damage dynamics and the diffraction signal. The results reveal that structural information is particularly well-preserved if the temporal distribution is skewed such that most photons are concentrated at the beginning.

While many obstacles remain, the prospect of atomic-resolution SPI is drawing ever closer. This thesis is but one of the stepping stones necessary to get us there. Once we do, the possibilities are limitless.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 84
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1815
Keywords [en]
X-ray free-electron laser, X-ray imaging, Single particle imaging, Computer simulation, Radiation damage, Molecular dynamics, Diffraction theory, Coulomb explosion, Sample heterogeneity, Diffractive noise, XFEL, SPI
National Category
Biophysics
Research subject
Physics with specialization in Biophysics
Identifiers
URN: urn:nbn:se:uu:diva-382441ISBN: 978-91-513-0669-8 (print)OAI: oai:DiVA.org:uu-382441DiVA, id: diva2:1307570
Public defence
2019-06-14, Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 10:15 (English)
Opponent
Supervisors
Funder
Swedish Research CouncilAvailable from: 2019-05-23 Created: 2019-04-28 Last updated: 2019-06-18
List of papers
1. Reproducibility of Single Protein Explosions Induced by X-ray Lasers
Open this publication in new window or tab >>Reproducibility of Single Protein Explosions Induced by X-ray Lasers
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2018 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 20, no 18, p. 12381-12389Article in journal (Refereed) Published
Abstract [en]

Single particle imaging (SPI) using X-ray pulses has become increasingly attainable with the advent of high-intensity free electron lasers. Eliminating the need for crystallized samples enables structural studies of molecules previously inaccessible by conventional crystallography. While this emerging technique already demonstrates substantial promise, some obstacles need to be overcome before SPI can reach its full potential. One such problem is determining the spatial orientation of the sample at the time of X-ray interaction. Existing solutions rely on diffraction data and are computationally demanding and sensitive to noise. In this in silico study, we explore the possibility of aiding these methods by mapping the ion distribution as the sample undergoes a Coulomb explosion following the intense ionization. By detecting the ions ejected from the fragmented sample, the orientation of the original sample should be possible to determine. Knowledge of the orientation has been shown earlier to be of substantial advantage in the reconstruction of the original structure. 150 explosions of each of twelve separate systems – four polypeptides with different amounts of surface bound water – were simulated with molecular dynamics (MD) and the average angular distribution of carbon and sulfur ions was investigated independently. The results show that the explosion maps are reproducible in both cases, supporting the idea that orientation information is preserved. Additional water seems to restrict the carbon ion trajectories further through a shielding mechanism, making the maps more distinct. For sulfurs, water has no significant impact on the trajectories, likely due to their higher mass and greater ionization cross section, indicating that they could be of particular interest. Based on these findings, we conclude that explosion data can aid spatial orientation in SPI experiments and could substantially improve the capabilities of the novel technique.

Keywords
XFEL, Single-particle imaging, Coulomb explosion, ultrafast, GROMACS, simulation.
National Category
Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:uu:diva-329340 (URN)10.1039/C7CP07267H (DOI)000431825300006 ()
Funder
Swedish Research Council, 2013-3940Swedish Foundation for Strategic Research Carl Tryggers foundation
Available from: 2017-09-13 Created: 2017-09-13 Last updated: 2019-04-28Bibliographically approved
2. Is Radiation Damage the Limiting Factor in Single Particle Imaging with X-ray Free-Electron Lasers?
Open this publication in new window or tab >>Is Radiation Damage the Limiting Factor in Single Particle Imaging with X-ray Free-Electron Lasers?
2019 (English)In: Structural Dynamics, E-ISSN 2329-7778, Vol. 6, article id 044103Article in journal (Refereed) Published
Abstract [en]

The prospect of single particle imaging with atomic resolution is one of the scientific drivers for the development of X-ray free-electron lasers. The assumption since the beginning has been that damage to the sample caused by intense X-ray pulses is one of the limiting factors of coherent diffractive imaging of single particles and that X-ray pulses need to be as short as possible. Based on molecular dynamics simulations of proteins in X-ray fields of various durations (5 fs, 25 fs and 50 fs), we show that the noise in the diffracted signal caused by radiation damage is less than what can be expected from other sources, such as sample inhomogeneity and X-ray shot-to-shot variations. These findings show a different aspect of the feasibility of single particle imaging using free-electron lasers, where employing X-ray pulses of longer durations could still provide a useful diffraction signal above the noise due to the Coulomb explosion.

Keywords
X-ray free electron laser, XFEL, X-ray diffraction, Ultrafast imaging, Coherent diffractive imaging, CDI, Single particle imaging, Computer simulation, Molecular dynamics, GROMACS, Radiation damage, Coulomb explosion
National Category
Biophysics
Identifiers
urn:nbn:se:uu:diva-382432 (URN)10.1063/1.5098309 (DOI)000492051300004 ()31463335 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)Swedish National Infrastructure for Computing (SNIC), snic2016-7-61
Available from: 2019-04-25 Created: 2019-04-25 Last updated: 2019-11-15Bibliographically approved
3. Sample Heterogeneity in Single Particle Imaging Using X-ray Lasers
Open this publication in new window or tab >>Sample Heterogeneity in Single Particle Imaging Using X-ray Lasers
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(English)Manuscript (preprint) (Other academic)
Keywords
X-ray free-electron laser, XFEL, Coherent diffractive imaging, CDI, Molecular dynamics, Single particle imaging, X-ray diffraction, Sample heterogeneity, Noise
National Category
Biophysics
Identifiers
urn:nbn:se:uu:diva-382437 (URN)
Funder
Swedish Research CouncilThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Available from: 2019-04-25 Created: 2019-04-25 Last updated: 2019-04-28
4. Simulations of Radiation Damage as a Function of the Temporal Pulse Profile in Femtosecond X-ray Protein Crystallography
Open this publication in new window or tab >>Simulations of Radiation Damage as a Function of the Temporal Pulse Profile in Femtosecond X-ray Protein Crystallography
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2015 (English)In: Journal of Synchrotron Radiation, ISSN 0909-0495, E-ISSN 1600-5775, Vol. 22, no 2, p. 256-266Article in journal (Refereed) Published
Abstract [en]

Serial femtosecond X-ray crystallography of protein nanocrystals using ultrashort and intense pulses from an X-ray free-electron laser has proved to be a successful method for structural determination. However, due to significant variations in diffraction pattern quality from pulse to pulse only a fraction of the collected frames can be used. Experimentally, the X-ray temporal pulse profile is not known and can vary with every shot. This simulation study describes how the pulse shape affects the damage dynamics, which ultimately affects the biological interpretation of electron density. The instantaneously detected signal varies during the pulse exposure due to the pulse properties, as well as the structural and electronic changes in the sample. Here ionization and atomic motion are simulated using a radiation transfer plasma code. Pulses with parameters typical for X-ray free-electron lasers are considered: pulse energies ranging from 10$\sp 4$ to 10$\sp 7$Jcm$\sp $-$2$ with photon energies from 2 to 12keV, up to 100fs long. Radiation damage in the form of sample heating that will lead to a loss of crystalline periodicity and changes in scattering factor due to electronic reconfigurations of ionized atoms are considered here. The simulations show differences in the dynamics of the radiation damage processes for different temporal pulse profiles and intensities, where ionization or atomic motion could be predominant. The different dynamics influence the recorded diffracted signal in any given resolution and will affect the subsequent structure determination.

Keywords
X-ray free-electron laser, serial femtosecond crystallography, radiation damage, plasma simulations
National Category
Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:uu:diva-245210 (URN)10.1107/S1600577515002878 (DOI)000350641100007 ()
Available from: 2015-02-25 Created: 2015-02-25 Last updated: 2019-04-28
5. FreeDam – A Webtool for Free-Electron Laser-Induced Damage in Femtosecond X-ray Crystallography
Open this publication in new window or tab >>FreeDam – A Webtool for Free-Electron Laser-Induced Damage in Femtosecond X-ray Crystallography
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2018 (English)In: High Energy Density Physics, ISSN 1574-1818, Vol. 26, p. 93-98Article in journal (Refereed) Published
Abstract [en]

Over the last decade X-ray free-electron laser (XFEL) sources have been made available to the scientific community. One of the most successful uses of these new machines has been protein crystallography. When samples are exposed to the intense short X-ray pulses provided by the XFELs, the sample quickly becomes highly ionized and the atomic structure is affected. Here we present a webtool dubbed FreeDam based on non-thermal plasma simulations, for estimation of radiation damage in free-electron laser experiments in terms of ionization, temperatures and atomic displacements. The aim is to make this tool easily accessible to scientists who are planning and performing experiments at XFELs.

Keywords
FreeDam, non-local thermodynamic equilibrium, x-ray free-electron laser, radiation damage, serial femtosecond x-ray crystallography, Cretin, simulation, database
National Category
Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:uu:diva-329499 (URN)
Available from: 2017-09-17 Created: 2017-09-17 Last updated: 2019-04-28

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