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Structural Heterogeneity in Single Particle Imaging Using X-ray Lasers
Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics. University of Applied Sciences Technikum Wien, Höchstädtplatz 6, A-1200 Wien, Austria.
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
Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics. European XFEL GmbH, Holzkoppel 4, DE-22869 Schenefeld, Germany.ORCID iD: 0000-0002-2926-5702
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.ORCID iD: 0000-0003-0458-0623
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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.

Place, publisher, year, edition, pages
2020. Vol. 11, no 15, p. 6077-6083
National Category
Biophysics Atom and Molecular Physics and Optics
Identifiers
URN: urn:nbn:se:uu:diva-416668DOI: 10.1021/acs.jpclett.0c01144ISI: 000562064500038PubMedID: 32578996OAI: oai:DiVA.org:uu-416668DiVA, id: diva2:1455682
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC 2019/8-30EU, Horizon 2020, 801406Swedish Research Council, 201800740Australian Research Council, DP190103027Available from: 2020-07-28 Created: 2020-07-28 Last updated: 2024-01-09Bibliographically approved
In thesis
1. Simulations of ultrafast photon-matter interactions for molecular imaging with X-ray lasers
Open this publication in new window or tab >>Simulations of ultrafast photon-matter interactions for molecular imaging with X-ray lasers
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Biological structure determination has had new avenues of investigation opened due to the introduction of X-ray free-electron lasers (XFELs). These X-ray lasers provide an extreme amount of photons on ultrafast timescales used to probe matter, and in particular biomolecules. The high intensity of the X-rays destroys the sample, though not before structural information has been acquired. The unique properties of the probe provide the unprecedented opportunity to study the un-crystallized form of biological macromolecules, small crystals of biomolecules and their dynamics. 

In this work, we study processes in XFEL imaging experiments that could affect the achievable resolution of the protein structure in a diffraction experiment. Elastic scattering is the process which provides structural information and leaves the sample unperturbed. This interaction occurs far less often compared to damage inducing processes, such as photoabsorption, which leads to rapid ionization of the studied sample. By using density functional theory, we study the effect of ultrahigh charge states in small systems, such as amino acids and peptides, on the subsequent bond breaking and charge dynamics. Reproducible fragmentation patterns are studied in order to find features that could be understood in larger systems, such as proteins. 

Biomolecules are dynamical systems, and the currently used pulse duration is not short enough to outrun the movement of the atoms. The diffraction patterns acquired in an experiment are therefore an incoherent sum of slightly different conformations of the same system. Water can help to reduce these structural variations, but the water molecules themselves will then be a source of noise. Using classical molecular dynamics, we study the optimal amount of water that should be used to achieve the highest resolution. 

To simulate ultrafast molecular dynamics of larger systems such as proteins, we develop a hybrid Monte Carlo/molecular dynamics model. We utilize it to simulate the fragmentation dynamics of small proteins and investigate the possibility to extract structural information from the fragmentation patterns. For larger systems exposed to X-ray lasers, such as viruses and crystals, we develop a hybrid collisional-radiative and classical molecular dynamics approach. The method is used in several projects, both in theoretical studies and to support experiments conducted at XFEL facilities. In particular, we simulate the interaction of hexagonal ice with an X-ray laser, and show the structure makes a phase transition from the native crystal state to a plasma, while still partly retaining structural order. Furthermore, we note that the structural changes occur in an anisotropic manner, where different local structural configurations in ice decay on different time-scales. 

Preliminary experimental results show this anisotropic dynamics in an X-ray pump-probe serial femtosecond X-ray crystallography experiment performed on  I3C crystals. The real space dynamics as a function of probe delay given by our theoretical model and the experiment both show good agreement, where the iodine atoms exhibit correlated motion. The model is also used to calculate the expected atomic displacement and ionization in a hemoglobin crystal, revealing the time and length scales of the dynamics in the protein during the experiment. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 95
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 2353
Keywords
X-ray free-electron laser, molecular dynamics, radiation damage, plasma simulations, density functional theory¸ coherent diffractive imaging, protein structure, X-ray crystallography, single particle imaging
National Category
Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:uu:diva-519472 (URN)978-91-513-2005-2 (ISBN)
Public defence
2024-02-29, Häggsalen, Ångström, Lägerhyddsvägen 1, Uppsala, 13:15 (English)
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Available from: 2024-02-08 Created: 2024-01-09 Last updated: 2024-02-08

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Mandl, ThomasÖstlin, ChristoferDawod, Ibrahim E.Brodmerkel, Maxim N.Marklund, ErikTimneanu, NicusorCaleman, Carl

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