Multiscale modelling of light harvesting, catalysis and ligand binding in biosystems
[eng] Biological processes are driven by dynamic mechanisms occurring across various timescales, from molecular interactions to large-scale conformational changes. This thesis explores how multiscale simulation techniques, integrating QM, MM, and QM/MM methods reveal the interplay of biological proc...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/221963 |
| Acceso en línea: | https://hdl.handle.net/2445/221963 http://hdl.handle.net/10803/694779 |
| Access Level: | acceso abierto |
| Palabra clave: | Enzimologia Catàlisi Lligands (Bioquímica) Modelització multiescala Dinàmica molecular Enzymology Catalysis Ligands (Biochemistry) Multiscale modeling Molecular dynamics |
| Sumario: | [eng] Biological processes are driven by dynamic mechanisms occurring across various timescales, from molecular interactions to large-scale conformational changes. This thesis explores how multiscale simulation techniques, integrating QM, MM, and QM/MM methods reveal the interplay of biological processes across different temporal and spatial scales, unraveling the dynamic mechanisms behind photosynthetic light harvesting, ligand-receptor interactions, and enzyme catalysis. In chapter 4 we explore the excitonic properties of photosynthetic pigment-protein complexes, specifically the Hemiselmis virescens PC612 and Chroomonas sp. PC645, which exhibit open and closed quaternary structures, respectively. Using a dual molecular dynamics (MD) protocol that combines classical MD and Born- Oppenheimer QM/MM simulations, we analyze the influence of thermal dynamics on excitonic interactions and spectral properties. The findings highlight the critical role of thermal fluctuations in shaping the light-harvesting efficiency of PC645, while PC612 demonstrates minimal spectral sensitivity to such effects. These results emphasize the importance of incorporating thermal effects in studying photosynthetic complexes and pave the way for future investigations into their structural and functional dynamics. In chapter 5 we address the structural and functional characterization of Imidazoline type 2 receptors (I2-IRs), which are emerging as potential therapeutic targets for neurodegenerative procesess like Alzheimer’s and Parkinson’s diseases. Despite their therapeutic promise, little is known about their structural biology and ligand-binding mechanisms. Combining MDmix simulations, molecular docking, and MD simulations, we identified six new putative binding sites for the canonical I2 ligand 2-BFI across seventeen proteins highlighted in previous proteomics studies. This comprehensive approach not only recovered known binding sites, such as that in monoamine oxidase B (MAO-B), but also revealed novel interaction hotspots, offering novel insights into the structural biology of I2-IR and paving the ground for future drug development. Finally in chapter 6 we focus on the catalytic mechanism of dopamine oxidation by MAO-B and its allosteric modulation by 2-BFI. Combining extended MD simulations and ONIOM QM/MM methodologies, we investigated the hydride transfer mechanisms of dopamine oxidation, direct and two-step pathways. The results highlight the critical role of dopamine's orientation, electrostatic interactions, and stabilization in facilitating reaction intermediates. Additionally, 2-BFI was found to alter dopamine’s conformational preferences and potentially modulate the catalytic reaction through allosteric mechanisms. These findings contribute to understanding 2-BFI’s functional role as both a modulator of MAOB. This thesis integrates computational approaches across various scales and biological systems to uncover critical insights into light harvesting, enzymatic catalysis, and ligand-receptor interactions, advancing the understanding of fundamental biological processes and their potential biomedical and biotechnological applications. |
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