Ab initio molecular dynamics study of thiolate-protected gold clusters and their interaction with biomolecules

• Autores: Víctor Rojas Cervellera
• Directores de la Tesis: Elvira Guàrdia i Manuel (dir. tes.), Carme Rovira Virgili (dir. tes.)
• Lectura: En la Universitat Politècnica de Catalunya (UPC) ( España ) en 2015
• Idioma: inglés
• Tribunal Calificador de la Tesis: Pau Gorostiza Langa (presid.), Marino Arroyo Balaguer (secret.), Olga López Acebedo (voc.)
• Programa de doctorado: Programa Oficial de Doctorado en Física Computacional y Aplicada
• Materias:
  • Física
    • Química física
  • Química
    • Bioquímica
    • Química orgánica
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • Thiolate monolayer-protected gold clusters (AuMPCs) are being used in various biological and biomedical applications due to their unique physical and chemical properties. The fact that gold-sulphur bonds are very stable enables the binding of biomolecules in the surface of gold clusters through a cysteine, an amino acid that contains a thiol group (SH). Specific AuMPCs-peptide conjugates can cross the blood-brain barrier without altering its integrity, opening the door for the treatment of pathologies related to the central nervous system, such as Alzheimer or Parkinson. Moreover, AuMPCs represent an alternative to the traditional fluorescence-based biosensors, due to their optical properties and its ability to bind specific antigens when certain AuMPCs-antibody conjugates are used. Several synthetic approaches based on the reduction of gold salts have been proposed to synthesize AuMPCs. In 1951 Turkevich and co-workers used sodium citrate for the reduction of chloroauric acid. In 2002 a novel synthetic method was proposed, named solvated metal atom dispersion method. In this method, neutral gold atoms were mixed with alkanethiols, resulting in the formation of AuMPCs, and molecular hydrogen was detected. This finding, together with the first crystallization and X-ray structure determination of Au102(SR)44 by Jadzinsky et.al., triggered a debate in the field, since the protons that were initially present in alkanethiols were not found in the AuMPC structure. One of the main goals of the present Thesis is to elucidate where the alkanethiol hydrogens go during the formation of the AuMPC. To this aim, ab initio metadynamics have been used to unravel the molecular mechanism of the formation of AuMPCs departing from neutral gold clusters and alkanethiols (Chapter III). Key to the usage of AuMPCs as biosensors is the better knowledge of their optical properties. The HOMO-LUMO gap, is a physical parameter related with optical properties. Density Functional Theory (DFT) is extensively used to obtain a theoretical value of the HOMO-LUMO gap, although it is known to severely underestimate it with respect to the experimental values. Nevertheless, recent computational studies using DFT have reported values of the HOMO-LUMO gap of AuMPCs in a very close agreement with the experimental ones. However, a simplified model of the real system was used, raising the question whether the agreement between the theoretical and the experimental values is fortuitous due to a compensation of errors. Our goal is to obtain HOMO-LUMO gap values using the whole experimental systems, i.e. peptides as the protecting ligands of the gold core and water as solvent (Chapter IV) to demonstrate that only a realistic model, and not only the use of appropriate DFT functionals, can lead to values comparable to the experimental ones. In a first step for the understanding of the reactivity of AuMPCs towards proteins, in Chapter V we modelled the binding of AuMPC towards an antibody. This process, known as ligand exchange reaction, is used to label proteins with gold clusters, as reducing agents cannot be used when certain biomolecules are present. Our results show that the neighbouring amino acids of the cysteine that should bind to the gold cluster play an essential role in the reaction. Finally, we focus on the study of the mechanism of the enzymatic reaction of a glycoprotein, a-1,3-glycosyltransferase. In recent years, our group has investigated the mechanism of one family of glycosyltransferases (GTs), providing its catalytic itinerary. In this thesis we extend this study to another family of GTs to elucidate whether or not a common molecular mechanism operates for GTs. This study represents one step towards the modelling of the more complex glycosyltransferases immobilized by gold nanoparticles, a promising technique for the development of automated glycosynthesis. The theoretical methods used along this thesis are detailed in Chapter II.