Van Bronkhorst Ferreira, Alexandre;
(2025)
Sampling and Classifying High-Dimensional Conformational Free Energy Landscapes of Active Pharmaceutical Ingredients.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
We present a new method for calculating the high-dimensional conformational free energy landscapes of flexible drug-like molecules. Using Density Peaks Advanced’s density estimator, the free energy associated with individual configurations sampled from an enhanced sampling simulation can be calculated in a gridless manner, thus enabling the mapping of conformational ensembles in dimensionalities computationally inaccessible to grid-based methods. Due to the physics-based configurational sampling, conformers can be characterized by the configurations corresponding to the density peaks. The gridless nature of this method enables this characterization in the full dimensionality of a flexible molecule’s conformation space. This method can produce per-point free energy maps, which enable the study of conformational interchanges in a level of detail previously inaccessible. This method is initially demonstrated on molecules with 2, 4, and 11-dimensional conformational spaces and is presented alongside a set of consistency checks which enable the quality of the high-dimensional results to be assessed. Finally, to further demonstrate the utility of the method, a study of the conformational landscapes of 4 different molecules is presented. Each molecule is subjected to two distinct solvent environments, which have been linked experimentally to conformational changes in these systems. The subsequent impact on the high-dimensional free energy landscapes is explored through the use of Sketch-map projections and visual inspections of the conformers generated by the method.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Sampling and Classifying High-Dimensional Conformational Free Energy Landscapes of Active Pharmaceutical Ingredients |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Chemical Engineering |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10212112 |
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