Computational modelling to study medium effect over molecules and biopolymers of interest in biomedicine
[eng] Computational simulation technologies facilitate the resolution of complex biomedical problems by helping researchers predict what will happen in a natural system in response to various external conditions. The main objective of this thesis project was to analyze, through computational modelli...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/203883 |
| Acceso en línea: | https://hdl.handle.net/2445/203883 http://hdl.handle.net/10803/689422 |
| Access Level: | acceso abierto |
| Palabra clave: | Quimioinformàtica Dinàmica molecular Simulació per ordinador Cheminformatics Molecular dynamics Computer simulation |
| Sumario: | [eng] Computational simulation technologies facilitate the resolution of complex biomedical problems by helping researchers predict what will happen in a natural system in response to various external conditions. The main objective of this thesis project was to analyze, through computational modelling, the effect of the environment on molecules and biopolymers of interest in biomedicine. The first objective was to analyze the resistance to denaturation of the macromolecular structure of Helicobacter pylori urease at acidic pHs. The second objective was focused on analyzing the structural stability of the main protease of SARS-CoV-2 at low pHs and the binding to the drug PF-00835231. The third objective was to analyze the affinity of SARS-CoV-2 Spike-S1 variants to ACE2, considering five pHs. The fourth objective was to analyze the congregation of phenylalanine monomers at physiological temperature. The last objective was to analyze sodium citrate on different concentrations of the solvents diethylene glycol and ethylene glycol. The computational methodology used in this thesis work used the Semi-Grand-Canonical Monte Carlo procedure to assign the charge state for each residue of the proposed macromolecules according to the individual pka obtained by the PROPKA program. It was adapted from a homemade computer program capable of predicting the protonation states of titratable protein residues under different pH conditions. The new adaptation can be found at the link hWps://github.com/smadurga/Protein-Protonation. Subsequently, atomistic simulations of all atoms with explicit solvent were applied for all the proposed systems. Finally, the binding free energy was calculated by MM/GBSA for the systems of five variants of Spike-S1 versus ACE2. The results of the Spike-S1 – ACE2 variants at different pHs demonstrated that mutations located in the Spike-S1 binding areas contribute to beWer binding to ACE2. The omicron variant has mutations that allow its binding to ACE2 at acidic and alkaline pHs. The results of molecular dynamics simulations of phenylalanine monomers at physiological temperature helped us understand the self-assembly of phenylalanine mediated by non- covalent interactions such as hydrogen bonds and pi-pi bonds between aromatic rings. The study of citrate showed that it maintained a gauche+ or gauche- orientation in the proposed solvents, while the dispersion of sodium ions was around the citrate, occupying an orientation close to its central carboxylate anion. In parallel, more hydrogen bonds were observed between citrate and pure diethylene glycol than pure ethylene glycol. Citrate has a high dipole moment when combined with pure diethylene glycol, where numerous hydrogen bond connections between both molecules cause this significant dipole moment. In conclusion, computational tools are very useful for understanding different biological environments where new insights were achieved on the behaviour of molecules and biopolymers of importance in biomedicine |
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