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A hybrid approach to study large conformational transitions of biomolecules from single particle XFEL diffraction data

X-ray free-electron laser (XFEL) is the latest generation of the X-ray source that could become an invaluable technique in structural biology. XFEL has ultrashort pulse duration, extreme peak brilliance, and high spatial coherence, which could enable the observation of the biological molecules in ne...

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Autores principales: Asi, Han, Dasgupta, Bhaskar, Nagai, Tetsuro, Miyashita, Osamu, Tama, Florence
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9846856/
https://www.ncbi.nlm.nih.gov/pubmed/36660427
http://dx.doi.org/10.3389/fmolb.2022.913860
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author Asi, Han
Dasgupta, Bhaskar
Nagai, Tetsuro
Miyashita, Osamu
Tama, Florence
author_facet Asi, Han
Dasgupta, Bhaskar
Nagai, Tetsuro
Miyashita, Osamu
Tama, Florence
author_sort Asi, Han
collection PubMed
description X-ray free-electron laser (XFEL) is the latest generation of the X-ray source that could become an invaluable technique in structural biology. XFEL has ultrashort pulse duration, extreme peak brilliance, and high spatial coherence, which could enable the observation of the biological molecules in near nature state at room temperature without crystallization. However, for biological systems, due to their low diffraction power and complexity of sample delivery, experiments and data analysis are not straightforward, making it extremely challenging to reconstruct three-dimensional (3D) structures from single particle XFEL data. Given the current limitations to the amount and resolution of the data from such XFEL experiments, we propose a new hybrid approach for characterizing biomolecular conformational transitions by using a single 2D low-resolution XFEL diffraction pattern in combination with another known conformation. In our method, we represent the molecular structure with a coarse-grained model, the Gaussian mixture model, to describe large conformational transitions from low-resolution XFEL data. We obtain plausible 3D structural models that are consistent with the XFEL diffraction pattern by deforming an initial structural model to maximize the similarity between the target pattern and the simulated diffraction patterns from the candidate models. We tested the proposed algorithm on two biomolecules of different sizes with different complexities of conformational transitions, adenylate kinase, and elongation factor 2, using synthetic XFEL data. The results show that, with the proposed algorithm, we can successfully describe the conformational transitions by flexibly fitting the coarse-grained model of one conformation to become consistent with an XFEL diffraction pattern simulated from another conformation. In addition, we showed that the incident beam orientation has some effect on the accuracy of the 3D structure modeling and discussed the reasons for the inaccuracies for certain orientations. The proposed method could serve as an alternative approach for retrieving information on 3D conformational transitions from the XFEL diffraction patterns to interpret experimental data. Since the molecules are represented by Gaussian kernels and no atomic structure is needed in principle, such a method could also be used as a tool to seek initial models for 3D reconstruction algorithms.
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spelling pubmed-98468562023-01-18 A hybrid approach to study large conformational transitions of biomolecules from single particle XFEL diffraction data Asi, Han Dasgupta, Bhaskar Nagai, Tetsuro Miyashita, Osamu Tama, Florence Front Mol Biosci Molecular Biosciences X-ray free-electron laser (XFEL) is the latest generation of the X-ray source that could become an invaluable technique in structural biology. XFEL has ultrashort pulse duration, extreme peak brilliance, and high spatial coherence, which could enable the observation of the biological molecules in near nature state at room temperature without crystallization. However, for biological systems, due to their low diffraction power and complexity of sample delivery, experiments and data analysis are not straightforward, making it extremely challenging to reconstruct three-dimensional (3D) structures from single particle XFEL data. Given the current limitations to the amount and resolution of the data from such XFEL experiments, we propose a new hybrid approach for characterizing biomolecular conformational transitions by using a single 2D low-resolution XFEL diffraction pattern in combination with another known conformation. In our method, we represent the molecular structure with a coarse-grained model, the Gaussian mixture model, to describe large conformational transitions from low-resolution XFEL data. We obtain plausible 3D structural models that are consistent with the XFEL diffraction pattern by deforming an initial structural model to maximize the similarity between the target pattern and the simulated diffraction patterns from the candidate models. We tested the proposed algorithm on two biomolecules of different sizes with different complexities of conformational transitions, adenylate kinase, and elongation factor 2, using synthetic XFEL data. The results show that, with the proposed algorithm, we can successfully describe the conformational transitions by flexibly fitting the coarse-grained model of one conformation to become consistent with an XFEL diffraction pattern simulated from another conformation. In addition, we showed that the incident beam orientation has some effect on the accuracy of the 3D structure modeling and discussed the reasons for the inaccuracies for certain orientations. The proposed method could serve as an alternative approach for retrieving information on 3D conformational transitions from the XFEL diffraction patterns to interpret experimental data. Since the molecules are represented by Gaussian kernels and no atomic structure is needed in principle, such a method could also be used as a tool to seek initial models for 3D reconstruction algorithms. Frontiers Media S.A. 2022-08-29 /pmc/articles/PMC9846856/ /pubmed/36660427 http://dx.doi.org/10.3389/fmolb.2022.913860 Text en Copyright © 2022 Asi, Dasgupta, Nagai, Miyashita and Tama. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Asi, Han
Dasgupta, Bhaskar
Nagai, Tetsuro
Miyashita, Osamu
Tama, Florence
A hybrid approach to study large conformational transitions of biomolecules from single particle XFEL diffraction data
title A hybrid approach to study large conformational transitions of biomolecules from single particle XFEL diffraction data
title_full A hybrid approach to study large conformational transitions of biomolecules from single particle XFEL diffraction data
title_fullStr A hybrid approach to study large conformational transitions of biomolecules from single particle XFEL diffraction data
title_full_unstemmed A hybrid approach to study large conformational transitions of biomolecules from single particle XFEL diffraction data
title_short A hybrid approach to study large conformational transitions of biomolecules from single particle XFEL diffraction data
title_sort hybrid approach to study large conformational transitions of biomolecules from single particle xfel diffraction data
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9846856/
https://www.ncbi.nlm.nih.gov/pubmed/36660427
http://dx.doi.org/10.3389/fmolb.2022.913860
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