Aplicación de la técnica de dinámica molecular al estudio de diferentes sistemas químicos supramoleculares

Abstract

This Thesis is devoted to the study of different supramolecular systems using the molecular dynamics simulation technique. In chapter II, we present the basis of Molecular Dynamics and its limitations in supramolecular system simulations. The physicochemical study of various systems usually relies on the measurement of their properties in relation to different experimental techniques. However, the experimental techniques used present limitations; i.e., some techniques do not provide direct information on the properties studied, while other techniques disturb the conditions of the systems during the measurements. In this sense, nowadays, thanks to the development of more sophisticated computers and new algorithms more and more efficients, Molecular Dynamics (MD) emerges as a powerful tool in the study of increasingly complex systems. In those conditions, the simulation techniques are the appropriate method to study certain systems at atomic level and provide reliable predictions [1]. MD simulation is a technique used for computing the equilibrium and dynamic properties of a classical system given that the dynamic of all particles obeys the laws of classical mechanics. This technique is a reliable method to understand and analyse the microscopic factors responsible for the macroscopic behaviour of a particular system [2]. In this chapter we also introduce a summary of the Molecular Dynamics algorithm and perform a brief description of the properties studied throughout thiswork. In chapter III, we pay close attention to the molecular mechanism of action of an anesthetic molecule on lipid bilayers. In the first section we briefly introduce anesthesia, its physiological effects and its proposed mechanism of action. The existence of molecules with anesthetic activity is known for over a century, which have been widely used in surgery due to its physiological reactions, such as reversible loss of consciousness, muscle relaxation, amnesia and pain relief. Although, the molecular mechanism by which those molecules act is not still fully known [3-8]. In this sense, there exist two different molecular theories that have been proposed: 1. Anesthetic molecules disrupt the cell membrane structure and consequently alter specific properties [9-12], which leads to the physiological effects of anesthesia. In particular, it has been proposed a physical mechanism by which a variation in the pressure profile across the membrane blocks ion transport through sodium channel [13, 14], due to a structural disturbance of the pore that forms the ion channel. This mechanism has been widely proposed on the grounds of the direct correlation between the solubility of the anesthetic molecules in hydrocarbon solvent and its pharmacological activity (Meyer-Overton law) [15-18]. 2. The anesthetic molecules have a direct bearing on the function of specific proteins that form the ion channels, closing the flux of ions through the cell membrane and blocking the electrical impulses in the nervous system [19]. In the second section of chapter Ill we describe the structure of the biological membrane and we analyse the fluid mosaic model [20] for the distribution of the phospholipids in a bilayer. In nature, biological membranes are an assembly of a diverse set of molecules such as lipids, sterols and proteins [21]. Focusing on the phospholipids that form the backbone of a lipid bilayer, they can be of different nature, charge and symmetrically or asymmetrically distributed between two layers of the lipid bilayer. For example, the inner layer of the erythrocytes (red blood cells) membrane is fundamentally constituted by phosphatidylserine (PS) with a minor amount of phosphatidylcholine (PC) and sphingomyelin, while only PC and sphingomyelin are present in the outermost layer [22-25]. Phospholipids forming lipid bilayers are molecules with a clear amphiphilic character (with hydrophobic and hydrophilic nature in the same molecule) that form flat structures. The hydrophilic part of lipids is in contact with the aqueous medium while the hydrophobic part is located within the bilayer [21, 26]. In a subsequent section of this chapter we describe the MD simulations conditions and the proposed molecular models. In this study, the lipid bilayers were modeled using different amounts of dipalmitoylphosphatidylcholine (DPPC) as a neutral lipid and dipalmitoylphosphatidylserine (DPPS-) as a negatively charged lipid in physiological conditions and benzocaine as the anesthetic. Benzocaine is a local anesthetic widely used in topical treatments since it presents a low water solubility [27,28] and a low pKa, i.e., it is always present in its neutral form under physiological conditions [29]. In this sense, this study focus on determine the static and dynamic properties of benzocaine located within the bilayers and understand its effect on the structure of the bilayer, for symmetrical and asymmetrical bilayer models, given that the lipid composition has been related with the pharmacological activity of benzocaine. In chapter IV we focus on the study of the electroactive (conductive) polymers/solution interface, as a function of the oxidation state of the polymer. After a brief introduction on conducting polymers and specific on polypyrrole (PPy), we describe the molecular models employed, the configuration of the system and the simulation parameters. The systems were modeled representing two different states of oxidation (a reduced state with neutral charge and an oxidized state with a positive charge) so as to determine the static and dynamic properties of the components of the systems, such as ions (perchlorate and lithium), the solvent (acetonitrile) and the polymer (polypyrrole). In the final section of the chapter IV, we present the results for the reduced and the oxidized polypyrrole in an 0.1 N lithium perchlorate solution in acetonitrile, where we focus on the study of different properties of all components in the system so as to examine how the oxidation state of the polypyrrole affects those properties at the interface. To characterize the polymer/solution interface we determine - among other properties - the atomic density and the charge distribution of the different components, as well as the variation in dynamic properties of ions and solvent (properties such as translational diffusion coefficient and solvation number). We also determine the spontaneity of the penetration process of the solvent molecules inside the polymer (as a function of its oxidation state) through thermodynamic calculations. In chapter V, we analyse different molecular models of the umami taste receptor. In the first sections of this chapter we briefly introduce the history of the umami taste and we shortly describe its taste receptor. In the early twentieth century, it was identified a fifth taste that did not resemble any of the familiar flavours (salty, sweet, sour and bitter), called the UMAMI taste or protein taste, which is easily identified in oriental cuisine. The umami taste has been linked with the monosodium glutamate (MSG) [30] which can be produced from the fermentation of sugars by microorganisms. The umami taste receptor is a Class C G protein coupled receptor (GPCR [30]), which responds to L-glutamate in humans diet [31, 32]. The receptor is a heterodimer composed of the T1 R1 and Ti R3 members of the T1 R family. Next, we present the results obtained on the study of the umami receptor conformation, being the main objective in this chapter to determine the active center of monosodium glutamate receptor responsible for the umami taste. The recent identification of the proteins that form the T1 R1 and T1 R3 receptors [33] make possible this study. Once known the crystallographic structures of the proteins that are the backbone of the receptor, we characterize the umami taste receptor by calculating the free energy of glutamate binding to the receptor. In chapter VI, VII and VIII, we draw the main conclusions of this Thesis, present some additional information as appendix and we comprise a list of the literature references used to conduct this research.