A path collective variable for extracting free energy profiles from cryo-electron microscopy

dc.contributorCossio Tejada, Pilar
dc.contributorRestrepo Cárdenas, Johans Steeven
dc.creatorGiraldo Barreto, Julian David
dc.date2022-07-14T19:23:42Z
dc.date2022-07-14T19:23:42Z
dc.date2021
dc.date.accessioned2023-08-28T20:53:53Z
dc.date.available2023-08-28T20:53:53Z
dc.identifierhttps://hdl.handle.net/10495/29739
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8485793
dc.descriptionABSTRACT: Cryo-electron microscopy (or cryo-EM) is an experimental technique to obtain structures of biomolecules. Although single-particle cryo-EM is widely used for 3D reconstruction, it has the potential to provide information about a biomolecule’s conformational variability, which leads to the underlying free-energy landscape of the system. However, cryo-EM as a single-molecule technique uses the 2D projections of individual particles with low signal-to-noise ratio (SNR), making it difficult to work directly with the raw cryo-EM data. Even though there are some methods that overcome the SNR issue, those normally need a big image data bank or are difficult to reproduce. This work proposes a new method called cryo-BIFE (cryo-EM Bayesian Inference of Free-Energy profiles), which uses a path collective variable to extract free-energy profiles and their uncertainties from cryo-EM images. The method is tested for different realistic experimental conditions, leading to a very good performance of extracting free energy profiles for different benchmark systems using different sets of synthetic images. The results show that, to recover the underlying free energy, the SNR in the cryoEM images and the accuracy in estimating the orientation of biomolecule’s projection, are crucial factors. Then, the method is used to study the conformational transitions of a calcium-activated channel with real cryo-EM particles. Interestingly, we recover not only the most probable conformation (used to generate a high-resolution reconstruction of the calcium-bound state) but also a metastable state that corresponds to the calcium-unbound conformation. As expected for turnover transitions within the same sample, the activation barriers are on the order of kBT. We expect our tool for extracting free-energy profiles from cryo-EM images will enable more complete characterization of the thermodynamic ensemble of biomolecules.
dc.format49
dc.formatapplication/pdf
dc.formatapplication/pdf
dc.languageeng
dc.publisherGrupo de Magnetismo y Simulación
dc.publisherMedellín - Colombia
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rightsAtribución-NoComercial-CompartirIgual 2.5 Colombia (CC BY-NC-SA 2.5 CO)
dc.rightshttp://creativecommons.org/licenses/by-nc-sa/2.5/co/
dc.rightshttp://purl.org/coar/access_right/c_abf2
dc.rightshttps://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rightshttps://creativecommons.org/licenses/by-nc-sa/4.0/
dc.subjectBiomolecules
dc.subjectCryoelectron microscopy
dc.subjectBayes theorem
dc.subjectSignal-to-noise ratio
dc.subjectMicroscopía por crioelectrón
dc.subjectTeorema de Bayes
dc.subjectRelación señal-ruido
dc.subjectBiomoléculas
dc.subjectFree energy profile
dc.subjectCryo-EM bayesian inference of free energy profiles (cryo-BIFE)
dc.subjectBayesian inference of electron microscopy (BioEM)
dc.subjecthttp://id.loc.gov/authorities/subjects/sh85014249
dc.subjecthttp://id.nlm.nih.gov/mesh/D020285
dc.subjecthttp://id.nlm.nih.gov/mesh/D001499
dc.subjecthttp://id.nlm.nih.gov/mesh/D059629
dc.titleA path collective variable for extracting free energy profiles from cryo-electron microscopy
dc.typeinfo:eu-repo/semantics/masterThesis
dc.typeinfo:eu-repo/semantics/draft
dc.typehttp://purl.org/coar/resource_type/c_bdcc
dc.typehttps://purl.org/redcol/resource_type/TM
dc.typeTesis/Trabajo de grado - Monografía - Maestría


Este ítem pertenece a la siguiente institución