Effects of impurities on crystal growth processes

Ph.DDOCTOR OF PHILOSOPH

The Structures and Properties of Protonated Phenylalanine Derivatives

Non-covalent interactions influence the 3-dimentional structures of large biomolecules. Hydrogen bonds, π-π stacking and cation-π interactions play a prominent role in protein folding and molecular recognition. In clusters peptide, and proteins that contain phenylalanine (Phe), the cation-π interaction arises from the interaction of the quadrupole charge distribution of the phenyl group with a positively charged species. By varying substituents around the phenyl ring one can potentially tune the cation-π interaction, even going so far as to invert the ring’s quadrupole moment, thus changing the cation binding motif. To explore the effects of electron donating/withdrawing groups on the non-covalent interactions of Phe clusters, ionic clusters including Phe, Phe derivatives, proton-bound dimers of Phe derivatives, and Phe dipeptide were investigated in a combined experimental and computational study. The low-lying isomers of various clusters of Phe were identified using the Basin-hopping (BH) search algorithm and optimized with density functional theory (DFT). The predicted harmonic vibrational spectra were then compared with experimental spectra obtained via infrared multiple photon dissociation (IRMPD) to determine cluster geometries

Advances in the theoretical determination of molecular structure with applications to anion photoelectron spectroscopy

This Dissertation is focussed primarily on development of methods aiming at the determination of molecular structures with application to systems with intra and intermolecular hydrogen bonds. I have developed and demonstrated usefulness of Potential Energy Surface Scanning Tool (PESST) by performing a systematic search for the most stable structures of neutral and anionic phenylalanine and tyrosine molecules using electronic structure methods. I have found out that tautomers resulting from the proton transfer from the carboxylic OH to phenyl ring determine the structure of the most stable anions of phenylalanine, but double proton transfer from the carboxylic and hydroxyl groups determine structures of the most stable anions of tyrosine. The most stable conformer of these valence anions remained adiabatically unbound with respect to the canonical neutral in case of phenylalanine but bound in case of tyrosine. Valence anions identified in this report have recently been observed experimentally. Acetoacetic acid (AA), equipped with neighbouring carboxylic and keto groups, is a promising system for studies of intramolecular proton transfer. The results of my computational search for the most stable tautomers and conformers of the neutral and anionic AA were used to interpret anion photoelectron and electron energy-loss spectroscopy measurements. The valence anion was identi ed in photoelectron spectroscopy experiments and the measured electron vertical detachment energy is in good agreement with my computational predictions. My computational results allow rationalizing these experimental findings in terms of the co-existence of various conformers of AA. I considered stability of dimers formed by molecules that can exist in different conformational states. I have developed a protocol that allows the dissection of the total stabilisation energy into one-body conformational and deformational components and the two-body interaction energy term. Interplay between these components determines the overall stability of the dimer. The protocol has been tested on the dimers of oxalic acid. The global minimum stability results from a balancing act between a moderately attractive two-body interaction energy and small repulsive one-body terms. I have analysed zero-point vibrational corrections to the stability of various conformers of oxalic acid and their dimers. I have found that minimum energy structures with the most stabilising sets of hydrogen bonds have the largest zero-point vibrational energy, contrary to a naive anticipation based on red shifts of OH stretching modes involved in hydrogen bonds. My computational results demonstrated an unusual electrophilicity of oxalic acid (OA), the simplest dicarboxylic acid. The electrophilicity results primarily from the bonding carbon-carbon interaction in the SOMO orbital of the anion, but it is further enhanced by intramolecular hydrogen bonds. The well-resolved structure in the photoelectron spectrum has been reproduced theoretically, based on Franck-Condon factors for the vibronic anion!neutral transitions. The excess electron binding energies in the dimer and trimer of OA become very signi cant due to intermolecular proton transfer, with the corresponding vertical detachment energy (VDE) values of approximately 3.3 and 4.6 eV. I have postulated a mechanism of excess electron mobility along molecular linear chains supported by cyclic hydrogen bonds. Searches for the most stable molecular conformer are frustrated by energy barriers separating minima on the potential energy surface (PES). I have suggested that the barriers might be suppressed by subtracting selected force field terms from the original PES. The resulting deformed PES can be used in standard molecular dynamics (MD) or Monte Carlo simulations. The MD trajectories on the original and deformed PESs of ethanolamine differ markedly. The former gets stuck in a local minimum basin while the latter moves quickly to the global minimum basin.(US) National Science Foundation grant CHE-111169

Direct Evidence for Tautomerization of the Uracil Moiety within the Pb2+/Uridine-5′-monophosphate Complex: A Combined Tandem Mass Spectrometry and IRMPD study

International audienc

Using ion-molecule reactions to probe the structure and reactivity of metal ion complexes with amino acids in the gas phase

Includes bibliographical references (pages [214]-238).Understanding the structure and reactivity of amino acids is necessary for the investigation of functionality and reactivity of proteins and peptides in biological systems. It has been determined that amino acids tend to be zwitterions at neutral pH. Previous electrospray ionization mass spectrometry (ESI-MS) studies have shown that gas-phase analysis of these amino acids can provide a means to determine the structure preference of a residue (i.e., charge solvation vs. zwitterion form). Computational investigations using the computer program Gaussian 03 were set up to theoretically model these ion-molecule interactions. Structural optimization and energetic information were obtained for both the [amino acid- M⁺] and [amino acid-M⁺-neutral] complexes. These data can be compared to the experimental ESI-MS data to corroborate findings. A series of ion-molecule reactions were used with ESI-MS to gather pertinent information. This analysis can be performed by introducing a volatile neutral species into the quadrupole ion trap of the mass spectrometer and allowing a reaction to occur between the neutral and an [amino acid-M⁺] complex. Rates determined from these kinetic experiments can then be used to correlate the structure and reactivity of the gas-phase [amino acid-M⁺] complex. Structural studies have confirmed that Pro is zwitterionic in the gas phase. Ala, Arg, and Lys are also likely to be zwitterions in the gas phase. Both Gly and His are found to be charge-solvated in the gas phase. It is also possible to analyze the reactivity of aromatic amino acids in a similar manner. Using pseudo-first-order kinetics, the equilibrium constant, K[sub eq], for these reactions was determined. From this value, the bond energy (ΔH) of the reaction was calculated. Aromatic amino acid reactivity studies have shown that there is a linear correlation between the theoretical stabilization energy (bond) 2 ‘b energy of [A. A.-H+Ca²⁺] with benzene and the proton affinity of the amino acids. Furthermore, experimental and theoretical experiments have shown that there is a direct correlation between the observed reaction efficiency and the theoretical stabilization energy of [A.A.+Cu⁺+toluene] complexes. Observed bonding energies for the [A.A.+Cu⁺+toluene] complexes were calculated to be between approximately 96 and 107 kJ mol⁻¹.Ph.D. (Doctor of Philosophy

An investigation of gas phase ion-molecule complexes involving novel binding modes

In this thesis, an innovative method is introduced to advance the study of gas phase clusters and used to analyse a number of novel binding modes. The systematic sampling of cluster surfaces (SSCS) routine, introduced in Chapter 3, is a computational technique that identifies cluster geometries by examining subsequent additions of solvent molecules along the surface of a core cluster. This technique examines the electrostatic potential of the solvent and cluster to determine favourable sites of interaction. This technique was found to result in a ten-fold increase in efficiency over common Monte-Carlo cluster geometry routines. Utilizing the SSCS routine, a highly debated topic in gas-phase chemistry was investigated, does electrospray ionization (ESI) sample gas phase or solution phase structures? This topic was investigated in Chapter 4, using deprotonated para-hydroxybenzoic acid and examined the solution phase (carboxylate deprotonated) and gas phase (phenoxide deprotonated) preferred tautomers. Numerous studies have argued for and against tautomer preference, while they missed an important underlying factor, do ESI spray conditions favour one or the other. Six solvents were selected to showcase the transition from the gas phase to the solution phase for one to five solvent molecules. This examination found that both protic and aprotic solvents showed a steady transition to ‘solution phase’ conditions at room temperature. Varying ESI spray conditions found an increase in temperature to result in reduced solution phase preference, with this effect being more drastic for some solvents than others. Thus, the importance of comparing ESI spray conditions is highlighted by this study wherein, electrospray ionization samples structures based off the energy available to the system on-route to the ion trap. In Chapter 5 and 6, all-cis hexafluorocyclohexane, all-cis pentafluorocyclohexanol, and all-cis hexa-trifluoromethyl-cyclohexane, were studied for their unique ability to bind both cationic and anionic species. It was found that these molecules possess significant dipole moments resulting in substantial propensity for binding ionic species and allowing for the formation of homogeneous dipole bound dimers. These dipole bound dimers were found to readily interact with both cationic and anionic species expanding the number of available binding motifs. These various features lend to a number of novel binding modes with ionic species in the gas phase. Lastly, Chapter 7 examines the cation-π interactions of inverse Sandwich Cyclopentadienyl Complexes of Sodium in the Gas Phase. This system was found to readily undergo cation-π interactions, with monomer, dimer, and trimer interactions all being found experimentally. The vibrational modes of these systems required a study of anharmonic vibrational modes due to their unconventional nature. Computational investigation found that as the inverse sandwich complexes grew in size, so too did the favourability for binding additional sandwich subunits. Computational limitations prevented the ability to determine at what size the system would no longer readily bind additional subunits

Investigations of peptide structural stability in vacuo

Gas-phase analytical techniques provide very valuable tools for tackling the structural complexity of macromolecular structures such as those encountered in biological systems. Conformational dynamics of polypeptides and polypeptide assemblies underlie most biological functionalities, yet great difficulties arise when investigating such phenomena with the well-established techniques of X-ray crystallography and NMR. In areas such as these ion mobility interfaced with mass spectrometry (IMMS) and molecular modelling can make a significant contribution. During an IMMS experiment analyte ions drift in a chamber filled with an inert gas; measurement of the transport properties of analyte ions under the influence of a weak electric field can lead to determination of the orientationally-averaged collision cross-section of all resolved ionic species. A comparison with cross-sections estimated for model molecular geometries can lead to structural assignments. Thus IMMS can be used effectively to separate gas-phase ions based on their conformation. The drift tube employed in the experiments described herein is thermally regulated, which also enables the determination of collision cross-sections over a range of temperatures, and can provide a view of temperature-dependent conformational dynamics over the experimental (low microsecond) timescale. Studies described herein employ IMMS and a gamut of other MS-based techniques, solution spectroscopy and – importantly – molecular mechanics simulations to assess a) conformational stability of isolated peptide ions, with a focus on small model peptides and proteins, especially the Trp cage miniprotein; and b) structural characteristics of oligomeric aggregates of an amyloidogenic peptide. The results obtained serve to clarify the factors which dominate the intrinsic stability of non-covalent structure in isolated peptides and peptide assemblies. Strong electrostatic interactions are found to play a pivotal role in determining the conformations of isolated proteins. Secondary structures held together by hydrogen bonding, such as helices, are stable in the absence of solvent, however gas-phase protein structures display loss of their hydrophobic cores. The absence of a polar solvent, “self-solvation” is by far the most potent force influencing the gas-phase configuration of these systems. Geometries that are more compact than the folded state observed in solution are routinely detected, indicating the existence of intrinsically stable compact non-native states in globular proteins, illuminating the nature of proteins’ ‘unfolded’ states

Theoretical and Experimental Study of Cooperativity Effects in Noncovalent Interactions

L’any 2002 tres grups de recerca, entre ells el nostre grup, van demostrar teòricament que la interacció entre anions i anells aromàtics electrodeficients, anomenada interacció anió–, era favorable. Des de llavors s’ha dut a terme un intens estudi de la seva naturalesa física fins la total comprensió. Aquesta tesi es basa amb l’estudi de la interacció anió– des de tres punts de vista. Primerament, la investigació es basa en el disseny teòric de motius estructurals per donar lloc a un receptor on la interacció anió– siga molt favorable, per posteriorment avaluar la força de la interacció experimentalment en dissolució. A continuació, es va analitzar la interrelació entre un gran nombre de combinacions d’interaccions no covalents. A partir d’aquest estudi es defineixen nous conceptes i es proposen diferents formules per calcular efectes de cooperativitat. Finalment, hem anat un pas més enllà en l’estudi de la interacció analitzant: 1) l’impacte de la interacció anió– a sistemes biològics; 2) la influència de modificacions a l’anió sobre la naturalesa física de la interacció.In 2002 three research groups, among them our research group, theoretically demonstrated that the interaction between anions and electron-deficient aromatic rings, named anion– interaction, was favourable. Since then, an intense study of its physical nature has been performed to understand it completely. This thesis is based on the study of the anion– interaction from three points of view. Firstly, theoretical design of binding units to build a receptor and to obtain the most favourable binding based on anion– interactions. The binding properties of these receptors have been experimentally assessed in solution. Secondly, we have studied the interplay between a great combination of noncovalent interactions. From this study, new concepts and formula to calculate cooperativity effects have been described. Finally, we have study one step further the anion– interaction analysing: 1) the impact of anion– interaction in biological systems; 2) how the modifications in the anion influence the physical nature of the interaction

Structure, energetics and reactions of metal cation complexes of dipeptides in the gas phase

Structure, energetics and reactions of ions in the gas phase can be revealed by mass spectrometry techniques coupled to ions activation methods. Ions can gain enough energy for dissociation by absorbing IR light photons introduced by an IR laser to the mass spectrometer. Also collisions with a neutral molecule can increase the internal energy of ions and provide the dissociation threshold energy. Infrared multiple photon dissociation (IRMPD) or sustained off-resonance irradiation collision-induced dissociation (SORI-CID) methods are combined with Fourier Transform Ion Cyclotron Resonance (FT-ICR) mass spectrometers where ions can be held at low pressures for a long time. The outcome of ion activation techniques especially when it is compared to the computational methods results is of great importance since it provides useful information about the structure, thermochemistry and reactivity of ions of interest. In this work structure, energetics and reactivity of metal cation complexes with dipeptides are investigated. Effect of metal cation size and charge as well as microsolvation on the structure of these complexes has been studied. Structures of bare and hydrated Na and Ca complexes with isomeric dipeptides AlaGly and GlyAla are characterized by means of IRMPD spectroscopy and computational methods. At the second step unimolecular dissociation reactions of singly charged and doubly charged multimetallic complexes of alkaline earth metal cations with GlyGly are examined by CID method. Also structural features of these complexes are revealed by comparing their IRMPD spectra with calculated IR spectra of possible structures. At last the unimolecular dissociation reactions of Mn complexes are studied. IRMPD spectroscopy along with computational methods is also employed for structural elucidation of Mn complexes. In addition the ion-molecule reactions of Mn complexes with CO and water are explored in the low pressures obtained in the ICR cell