title: Hybrid approach for structural modeling of biological systems from X-ray free electron laser diffraction patterns.
abstract: We present a new hybrid approach for structural modeling using X-ray free electron laser (XFEL) diffraction patterns from non-crystalline biological samples. Reconstruction of a 3D structure requires a large number of diffraction patterns; however, in the current XFEL experiments with biological systems, the analysis often relies on a small number of 2D diffraction patterns. In this study, we explore the strategies to identify plausible 3D structural models by combining the 2D analysis of such diffraction patterns with computational modeling (normal mode analysis or molecular dynamics simulations). As the first step toward such hybrid modeling, we established a protocol to assess the agreement between the model structure and the target XFEL diffraction pattern and showed that XFEL data can be used to study the conformational transitions of biological molecules. We tested the proposed algorithms using data of three biomolecular complexes of different sizes (elongation factor 2, CCM virus, and ribosome) and examined the experimental conditions that are required to perform such studies, in particular the XFEL beam intensity requirements. The results indicate that the current beam intensity is close to a strength that enables us to study conformational transitions of macromolecules, such as ribosomes. The proposed algorithm can be combined with molecular mechanics approaches, such as molecular dynamics simulations and normal mode analysis, to generate a large number of candidate structures to perform hybrid structural modeling.
authors.affiliation: RIKEN Advanced Institute for Computational Science, 6-7-1, Minatojima-minami-machi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tokuhisa
authors.affiliation: IMPMC, Sorbonne Universités - CNRS UMR 7590, UPMC Univ Paris 6, MNHN, IRD UMR 206, Paris 75005, France.
authors.forename: Slavica
authors.initials: S
authors.lastname: Jonic
authors.affiliation: RIKEN Advanced Institute for Computational Science, 6-7-1, Minatojima-minami-machi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; Department of Physics, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan.
authors.forename: Florence
authors.initials: F
authors.lastname: Tama
authors.affiliation: RIKEN Advanced Institute for Computational Science, 6-7-1, Minatojima-minami-machi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: osamu.miyashita@riken.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Miyashita
mesh_terms: D000465:Algorithms; D004583:Electrons; D036388:Ephrin-B2 / Q000737:chemistry; D007834:Lasers; D046911:Macromolecular Substances / Q000737:chemistry*; D008961:Models, Structural; D012270:Ribosomes / Q000737:chemistry; D012542:Scattering, Radiation; D014780:Viruses / Q000737:chemistry
chemical_list: D036388:Ephrin-B2; D046911:Macromolecular Substances
keywords: Coherent diffraction; Computational modeling; Conformational transitions; Diffraction pattern; Experimental conditions; Protein structure; XFEL