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However, structural information in HS-AFM images is limited to the surface geometry of a sample molecule. Inferring latent three-dimensional structures from the surface geometry is thus important for getting more insights into conformational dynamics of a target biomolecule. Existing methods for estimating the structures are based on the rigid-body fitting of candidate structures to each frame of HS-AFM images. Here, we extend the existing frame-by-frame rigid-body fitting analysis to multiple frames to exploit orientational correlations of a sample molecule between adjacent frames in HS-AFM data due to the interaction with the stage. In the method, we treat HS-AFM data as time-series data, and they are analyzed with the hidden Markov modeling. Using simulated HS-AFM images of the taste receptor type 1 as a test case, the proposed method shows a more robust estimation of molecular orientations than the frame-by-frame analysis. The method is applicable in integrative modeling of conformational dynamics using HS-AFM data.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010384","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T18:31:45Z","timestamp":1672338705000},"page":"e1010384","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Development of hidden Markov modeling method for molecular orientations and structure estimation from high-speed atomic force microscopy time-series images"],"prefix":"10.1371","volume":"18","author":[{"given":"Tomonori","family":"Ogane","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7024-2054","authenticated-orcid":true,"given":"Daisuke","family":"Noshiro","sequence":"additional","affiliation":[]},{"given":"Toshio","family":"Ando","sequence":"additional","affiliation":[]},{"given":"Atsuko","family":"Yamashita","sequence":"additional","affiliation":[]},{"given":"Yuji","family":"Sugita","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2872-3908","authenticated-orcid":true,"given":"Yasuhiro","family":"Matsunaga","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"pcbi.1010384.ref001","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1006\/meth.2001.1217","article-title":"Single-Molecule Fluorescence Resonance Energy Transfer","volume":"25","author":"T. 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