Toward refined theoretical models for the description of lipophilicity in biomolecules
- Autores: William J. Zamora Rodríguez
- Directores de la Tesis: Francisco Javier Luque Garriga (dir. tes.), Josep Maria Campanera Alsina (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: José Peral Pérez (presid.), Tiziana Ginex (secret.), Baldomero Oliva Miguel (voc.)
- Programa de doctorado: Programa de Doctorado en Biotecnología por la Universidad de Barcelona
- Materias:
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- Resumen
Toward Refined Theoretical Models for the Description of Lipophilicity in Biomolecules William J. Zamora Ramírez Summary Lipophilicity is a key physicochemical descriptor used to understand the biological profile of (bio)organic compounds, xenobiotics and a broad variety of biochemical, pharmacological, and toxicological processes. This property is estimated from the partition coefficient between aqueous and nonaqueous environments for neutral compounds (PN) and corrected for the pHdependence of ionizable compounds as the distribution coefficient (D). In this context, in this doctoral thesis the Miertus–Scrocco–Tomasi continuum solvation model was used to check the suitability of some reported and proposed formalisms to estimate the distribution coefficient for a set of small acidic and basic compounds. The results indicate that in general the simple pHdependence model of the ionizable compound in water suffices to predict the partitioning at or around physiological pH. However, at extreme pH values, where ionic species are predominant, more elaborate models provide a better prediction of pH-dependent distribution curves of log D for both acidic and basic compounds as well as for amino acid analogues. New theoretical treatments for the lipophilicity profile of ionizable compounds were proposed to account for the electroneutrality in the phases of the n-octanol/water system.
In this context, was used the theory of ion-transfer across the interface between two immiscible electrolyte solutions (ITIES). Experimental research is being carried out to see the scope of those formalisms developed in this thesis.
Taking advantage of the successful results in small compounds, a lipophilicity scale adapted to different pH conditions was built for the 20 natural amino. The environment-dependence was introduced from the Dunbrack’s backbonedependent conformational library using two weighting schemes for the rotamers: solvent-like (SolvL) and protein-like (ProtL) lipophilic schemes. The veracity of our scale was corroborated with successful correlations with other consolidated experimental scales. Characterization of short disordered peptides (retention times in RP-HPLC, log PN and log D7.4 values) was best described using the former approach, and biological properties of peptides with available three-dimensional structure (local context-dependent lipophilicity e.g binding free energies) with the second one. Our theoretical lipophilicity scale was thus characterized by its versatility and adaptability, which confers a unifying character. Future studies will address the application of this methodology to the calculation of lipophilic parameters for no proteogenic amino acids, other conformations of the actual residues (proline cis) and other fragments relevant to proteins. On the other hand, the applicability of the present versatile scale is vast and promising, including for instance the use as scorings for proteinprotein docking protocols, among others.
