Citation
Mai, Huanghao (2025) Advancing Structural Analysis with Computational Methods Development. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/4p95-d385. https://resolver.caltech.edu/CaltechTHESIS:07252024-205053475
Abstract
In this thesis, a set of computational methods is developed to extend structural techniques beyond their conventional practice. First, we build in silico simulations and image processing protocols to design a new data acquisition workflow in cryo-electron tomography. This enables in situ visualization of macromolecular complexes at sub-nanometer resolution in a micron-scale field of view. Then, we demonstrate the applicability of a novel machine-learning algorithm in processing small molecule electron diffraction data for the first time. For most molecules tested, the correct ab initio structures can be obtained without the common practice of manual dataset curation. Finally, molecular dynamics simulations using crystallographic structures of protein and drug molecule complexes are performed to investigate the fundamental principles of a ternary binding property. A minimal forcefield with multi-scale coarse-graining enables alchemical free energy calculations at an unconventional size of perturbation while providing physical insight into the role of the drug linker and protein shapes.
| Item Type: | Thesis (Dissertation (Ph.D.)) | |||||||||
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| Subject Keywords: | microED;cryoET;alchemical free energy calculations;Biophysics | |||||||||
| Degree Grantor: | California Institute of Technology | |||||||||
| Division: | Chemistry and Chemical Engineering | |||||||||
| Major Option: | Biochemistry and Molecular Biophysics | |||||||||
| Thesis Availability: | Not set | |||||||||
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| Defense Date: | 1 July 2024 | |||||||||
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| Record Number: | CaltechTHESIS:07252024-205053475 | |||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechTHESIS:07252024-205053475 | |||||||||
| DOI: | 10.7907/4p95-d385 | |||||||||
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| Default Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | |||||||||
| ID Code: | 16592 | |||||||||
| Collection: | CaltechTHESIS | |||||||||
| Deposited By: | Huanghao Mai | |||||||||
| Deposited On: | 30 Jul 2024 23:21 | |||||||||
| Last Modified: | 30 Jul 2024 23:21 |
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