Conformational properties of constrained proline analogues and their application in nanobiology

• Autores: Alejandra Flores Ortega
• Directores de la Tesis: Carlos Alemán Llansó (dir. tes.)
• Lectura: En la Universitat Politècnica de Catalunya (UPC) ( España ) en 2009
• Idioma: inglés
• Tribunal Calificador de la Tesis: Juan Jesús Pérez González (presid.), David Zanuy Gomara (secret.), Carlos Cativiela Marín (voc.), David Curco Cantarell (voc.), Eric A. Perpète (voc.)
• Materias:
  • Química
    • Química analítica
      • Análisis de polímeros
    • Bioquímica
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • This thesis is composed of two parts:We have used different computer simulation techniques to investigate the impact of different chemical modifications on the conformational preferences of proline and to examine the application of conformationally constrained proline analogues in Nanobiology.Specifically, the first part shows the conformational study of proline derivatives that were obtained by introducing one or more double bonds in the pyrrolidine ring, by replacing the α-hydrogen atom by an alkyl group or by incorporating a polar substituent at the β- or γ-position of the pyrrolidine ring. These conformational investigations were performed using Quantum Mechanical calculations at the DFT (Density Functional Theory) levels. Furthermore, the influence of the solvent on the preferences of the different proline derivatives was examined using the Polarizable Continuum Model (PCM).The second part of the work consists on the design of a constrained proline derive able to protect a tumor-homing peptide from the attack of proteases but retaining, or even enhancing, its intrinsic biological activity. For this purpose, the bioactive conformation of the tumor-homing peptide was determined and characterized using a computational strategy based on the combination of Simulated Annealing combined with Molecular Dynamics. After this, the designed proline was derivative was introduced in the biological peptide using a targeted replacement strategy. The efficiency of the synthetic derivative was examined in silico using classical force-field simulations.