Vibrational Probe and Methods Development for Studying the Ultrafast Dynamics of Preferential Solvation of Biomolecules by 2D-IR.

Over the last decade two-dimensional infrared spectroscopy (2D-IR) has emerged as a powerful method for the investigation of biological samples and their dynamics. Through the implementation of state of the art signal processing methods we have demonstrated a significant, 20-fold, reduction in the acquisition time of traditional 2D-IR spectra. This new technique, utilizing compressed sensing, compliments our previously developed RASD method, allowing for the rapid acquisition of complete 2D-IR spectra as opposed to dynamical information at a single excitation-detection frequency pair. Additionally we have realized the first biocompatible, modular, metal-carbonyl probes for 2D-IR utilizing benzyl-chromium tribarbonyls. This has enabled ultrafast 2D-IR investigations of lipids and preferential solvation in solutions and at site-specific locations within enzyme scaffolds. In aqueous solutions we find that preferential solvation by a polar cosolvent causes a slowdown of the observed dynamics sensed by our probes. From modeling our system this slowdown is found to be consistent with arising from the slow, ca. 8 ps, exchange dynamics between the polar co-solute and water in the vicinity of our probe. This interpretation of preferential solvation in solution is further able to describe the observed dynamical differences found at the protein-solvent interface in a model system. By studying a series of protein mutants we find, spectroscopically and through simulations, that interactions between the side chains and the solution are sufficient to modulate the degree of preferential solvation and therefore dynamics, within specific sites of the protein. This information provides a foundation on how to modulate of the diffusion of substrates and products into and out-of the active sites of enzymes, through directed mutation of their protein sequence. The diffusional motion of the solvent and substrates is often the rate-limiting step in enzymatic catalysis. By controlling the local solvation dynamics of enzymes, sequence mutations offer a method to fine-tune the dynamics of enzymes. The ability to characterize the site-specific solvation dynamics of enzymes in response to primary structure mutations, positions 2D-IR and our chromium tricarbonyl probes as powerful tools for understanding protein and enzyme dynamics. This provides insight into controlling the catalytic rate of enzymes through directed mutation.PhDBiophysicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111440/1/josefd_1.pd

Structure Property and Prediction of Novel Materials using Advanced Molecular Dynamics Techniques: Novel Carbons, Germaniums and High-Performance Thermoelectrics

By means of advanced molecular dynamic techniques, we predict the stability of novel materials based on carbon, germanium and PbSe. This topological solutions have been studied and characterised at a DFT/DFTB level of theory and interesting optical, mechanical, electronic and heat transport properties have been pointed out

AFLOW-SYM: Platform for the complete, automatic and self-consistent symmetry analysis of crystals

Determination of the symmetry profile of structures is a persistent challenge in materials science. Results often vary amongst standard packages, hindering autonomous materials development by requiring continuous user attention and educated guesses. Here, we present a robust procedure for evaluating the complete suite of symmetry properties, featuring various representations for the point-, factor-, space groups, site symmetries, and Wyckoff positions. The protocol determines a system-specific mapping tolerance that yields symmetry operations entirely commensurate with fundamental crystallographic principles. The self consistent tolerance characterizes the effective spatial resolution of the reported atomic positions. The approach is compared with the most used programs and is successfully validated against the space group information provided for over 54,000 entries in the Inorganic Crystal Structure Database. Subsequently, a complete symmetry analysis is applied to all 1.7$+$ million entries of the AFLOW data repository. The AFLOW-SYM package has been implemented in, and made available for, public use through the automated, $\textit{ab-initio}$ framework AFLOW.Comment: 24 pages, 6 figure

Investigation of the Pd(1−x)Znx alloy phase diagram using ab initio modelling approaches

The identification of the stable phases in alloy materials is challenging because composition affects the structural stability of different intermediate phases. Computational simulation, via multiscale modelling approaches, can significantly accelerate the exploration of phase space and help to identify stable phases. Here, we apply such new approaches to understand the complex phase diagram of binary alloys of PdZn, with the relative stability of structural polymorphs considered through application of density functional theory coupled with cluster expansion (CE). The experimental phase diagram has several competing crystal structures, and we focus on three different closed-packed phases that are commonly observed for PdZn, namely the face-centred cubic (FCC), body-centred tetragonal (BCT) and hexagonal close packed (HCP), to identify their respective stability ranges. Our multiscale approach confirms a narrow range of stability for the BCT mixed alloy, within the Zn concentration range from 43.75% to 50%, which aligns with experimental observations. We subsequently use CE to show that the phases are competitive across all concentrations, but with the FCC alloy phase favoured for Zn concentrations below 43.75%, and that the HCP structure favoured for Zn-rich concentrations. Our methodology and results provide a platform for future investigations of PdZn and other close-packed alloy systems with multiscale modelling techniques

The Power of Fragments: FBLD approach to investigate protein structures

Fragments are small chemical entities with the extraordinary advantage of belonging to a wide variety of functional groups able to explore various chemical spaces, penetrate small protein pockets and allow the mapping of various protein binding sites. Nowadays, fragment-based lead discovery (FBLD) is the method of choice to screen fragment libraries and plays an increasingly important role in the drug development process. It becomes therefore particularly important to have a general-purpose fragment library ready to use. In our group a 96-fragment library was validated on eight protein targets, which was designed in a joint project between the HZB MX-group at BESSY II (AG Weiss) and the Institute of Pharmaceutical Chemistry, University of Marburg (AG Klebe) (Part I). Among the eight validated proteins, there are Thermolysin (TLN, Part II) and Trypanosoma cruzi Farnesyl Pyrophosphate Synthase (T. cruzi FPPS, Part III) which were the main focus of the present study. The 96-fragment library was therefore used as primary X-ray crystallographic screening method to search for novel chemical scaffolds. However, a new soaking protocol had to be established prior to the fragment screening. In fact, unlike the typical TLN inhibitor, fragments usually have insufficient affinity to displace on their own the autoproteolitically product Val-Lys dipeptide which occupies the TLN active site. The protein crystals were therefore incubated in an isopropanol solution able to displace the dipeptide and subsequentially screened against the fragment library resulting in seven crystallographic fragment hits. Unlike TLN which is usually used as a model protein, T. cruzi FPPS is a key enzyme involved in the mevalonate pathway and is essential for sterol production. T. cruzi and T. brucei parasites cause Chagas disease (CD) and human African trypanosomiasis (HAT) respectively and inhibition of FPPS in these species is therefore a valid target to fight these two tropical diseases. The present work focused first on optimizing the stability of protein samples in solution using various techniques such as thermal shift assay (TSA) and light scattering (LS). A crystallization and soaking protocol were subsequently established prior to performing a crystallographic fragment screening of the above-mentioned 96 fragment library. In addition, the role of the magnesium ion as cofactor of the enzyme was also elucidated, either alone or in complex with isopentenyl pyrophosphate (IPP) or bisphosphonates (BPs). Based on the discovery by Jahnke et al. of a new allosteric pocket in human FPPS, it was assumed that a similar pocket was also present in the Trypanosoma species which was therefore the main target-site of the present work. The fragment screening project resulted in three crystallographic hits, one of which binding the allosteric pocket while the other two in a new pocket whose function is still unknown. They can serve as good candidates for the design of a new series of lead compounds. In addition to the 96-fragment library, other series of compounds of fragment-size were screened against Endothiapepsin (EP, Part IV) and different human Carbonic Anhydrase (hCA, Part V) isoforms. In particular, a series of tetrazole compounds were crystallographically screened against EP in order to validate a novel pipeline for the rapid development of novel aspartyl protease inhibitors using an anchoring approach. The hydrazide moiety was here chosen as fragment-anchor able to bind the catalytic dyad in the EP active site. Moreover, in addition to X-ray crystallography which was the dominant screening method used in the present thesis, a series of para-substituted benzenesulfonamide were screened against different hCAs isoforms using Surface Plasmon Resonance (SPR). According to Gaspari et al., the kinetics of binding of hCAII depend on the nature of the substituent that decorate the benzenesulfonamide moiety. In particular, the association rate kon becames faster by increasing the hydrophobic nature of the para-alkyl chain due to a pre-binding event. This finding was also confirmed in the present study. However, it seems that more than one features contribute to the trends in kon and koff. Furthermore, in contrast with hCAII, hCAXII showed a faster dissociation rate by increasing the length of the para-alkyl chain, probably due to the higher surface hydrophilicity. The nature of the surface around the active site of hCAs plays therefore an important role in the kinetics of binding. In conclusion, fragments are powerful molecules able to explore and discover new protein pockets, to evolve into more potent lead compounds and often they are used as starting point in several screening methods in the field of FBLD

Parameters optimization of a charge transport model for the electrical characterization of dielectric materials

Un modèle mathématique basé sur la physique des matériaux isolants a été développé dans notre laboratoire pour décrire le transport de charge bipolaire (BCT) dans le polyéthylène basse densité (LDPE) sous contrainte de courant continu. Les phénomènes de piégeage et de dé-piégeage, la hauteur de la barrière pour l'injection, la mobilité et le processus de recombinaison des charges positives et négatives sont considérés. Le modèle est basé sur l'équation de Poisson et la loi de conservation des charges. Ce modèle nécessite des entrées qui sont reliées aux conditions expérimentales telles que la température, la tension appliquée, l'épaisseur du diélectrique, etc., ainsi qu'un l'ensemble de paramètres tels que la barrière d'injection, la mobilité, les coefficients de piégeage et de dé-piégeage. La plupart de ces paramètres ne peuvent être prédits, observés ou estimés par des expériences indépendantes. Pour cette raison, un algorithme d'optimisation est utilisé pour optimiser le modèle BCT afin qu'il s'adapte aux mesures expérimentales, quelles que soient les conditions expérimentales. Le principe de ce type d'algorithme est basé sur la minimisation d'une fonction coût qui rend compte des écarts entre les données issues de l'expérience et celles issues du modèle. Les données expérimentales utilisées sont la densité de charge nette mesurée par la méthode électro-acoustique pulsée (PEA) ainsi que les mesures du courant de charge externe. Après avoir testé cinq algorithmes d'optimisation nous avons sélectionné l'algorithme Trust Region Reflective qui répond au mieux à nos critères. Cet algorithme a permis de trouver un ensemble de paramètres permettant une bonne corrélation entre les densités de courant et de charge simulées et celles obtenues expérimentalement. Cette optimisation a été réalisée en considérant différent champs électriques appliqués au matériau afin d'avoir un jeu de paramètre qui caractérise au mieux le matériau d'étude. En outre, l'algorithme d'optimisation a permis d'analyser la barrière d'injection lorsque les interfaces sont de natures différentes.A mathematical model based on the physics of insulating materials has been developed in our laboratory to describe the bipolar charge transport (BCT) in low-density polyethylene (LDPE) under DC stress. The phenomena of trapping and detrapping, the barrier height for injection, the mobility, and the recombination process of positive and negative charges are considered. The model is based on the Poisson equation and the law of conservation of charges. This model requires inputs that are related to the experimental conditions such as temperature, applied voltage, dielectric thickness, etc., as well as a set of parameters such as the injection barrier, mobility, trapping, and detrapping coefficients. Most of these parameters cannot be predicted, observed, or estimated by independent experiments. For this reason, an optimization algorithm is used to optimize the BCT model to fit the experimental measurements, whatever the experimental conditions, by minimizing the sum of squares of the deviations between the experimental data and the model data. The experimental data used are the net charge density measured by the pulsed electro-acoustic method (PEA) as well as the external charge current measurements. After testing five optimization algorithms we selected the following algorithm Trust Region Reflective which best meets our criteria. This algorithm has allowed us to find a set of parameters allowing a good correlation between the simulated current and charge densities with those obtained experimentally. This optimization was performed by considering different electric fields applied to the material in order to have a unique set of parameters that best characterizes the studied material. In addition, the optimization algorithm allowed to analyze the injection barrier when the interfaces are of different natures

Bulletin of Armstrong College Of Savannah 1957-1958

Academic catalog for Armstrong College of Savannah