Molecular Electronics

This is a Special Issue on Molecular Electronics which provides an overview of the field and will be useful for both theoreticians and experimentalists. Topics include protein-based electronics, field-induced trans-to-cis isomerisation, phonon thermal conductance, spin-dependent transport, attenuation factors, HOMO-LUMO gap corrections and nanofabrication techniques

INVESTIGATING THE EFFECTS OF IONIC LIQUIDS ON DNA GQUADRUPLEX AND PROTEIN STRUCTURE USING MOLECULAR DYNAMICS SIMULATIONS

Nucleic acids and proteins have huge implications in biomedicine and bioengineering, however their storage instability limits their applicability and current storage protocols are expensive and globally-inaccessible. Finding an alternative biocompatible media to store nucleic acids and proteins would reduce costs and increase their applicability. Ionic liquids (ILs) are molten salt compounds that have been shown to modulate the stability and activity of nucleic acids and proteins. In this thesis, molecular modeling studies of DNA/RNA and protein structure in ILs will be discussed (Chapter 1) and this method will be used to study the IL effects on the structure on the Pu22 c-MYC DNA G-quadruplex (Chapter 2) and the azurin protein (Chapter 3). ILs have been observed to stabilize/destabilize DNA G-quadruplexes linked to cancer oncogene expression, however the structural effects of imidazolium-based ILs on G-quadruplexes remain unknown. Bioengineering of azurin is attractive for soil bioremediation, thus understanding the structural changes induced by TMG amino acid-based ILs will mediate future IL design for enhancing azurin\u27s activity. In Chapter 2, molecular dynamics (MD) simulations will elucidate the stabilizing mechanism of four imidazolium-based ILs of increasing hydrophobicity to Pu22, using the G-quadruplex stabilizer TMPyP4 as a molecular probe. In Chapter 3, conventional and replica-exchange MD simulations will provide insight into the enthalpic and entropic change induced by two TMG-AA based ILs on the folded and unfolded azurin conformations

Competing ultrafast photoinduced electron transfer and intersystem crossing of [Re(CO)(3)(Dmp)(His124)(Trp122)]+ in Pseudomonas aeruginosa azurin:a nonadiabatic dynamics study

We present a computational study of sub-picosecond nonadiabatic dynamics in a rhenium complex coupled electronically to a tryptophan (Trp) side chain of Pseudomonas aeruginosa azurin, a prototypical protein used in the study of electron transfer in proteins. To gain a comprehensive understanding of the photoinduced processes in this system, we have carried out vertical excitation calculations at the TDDFT level of theory as well as nonadiabatic dynamics simulations using the surface hopping including arbitrary couplings (SHARC) method coupled to potential energy surfaces represented with a linear vibronic coupling model. The results show that the initial photoexcitation populates both singlet metal-to-ligand charge transfer (MLCT) and singlet charge-separated (CS) states, where in the latter an electron was transferred from the Trp amino acid to the complex. Subsequently, a complex mechanism of simultaneous intersystem crossing and electron transfer leads to the sub-picosecond population of triplet MLCT and triplet CS states. These results confirm the assignment of the sub-ps time constants of previous experimental studies and constitute the first computational evidence for the ultrafast formation of the charge-separated states in Re-sensitized azurin

In situ spectroelectrochemical investigations of electrode-confined electron transferring proteins and redox enzymes

This perspective analyzes recent advances in the spectroelectrochemical investigation of redox proteins and enzymes immobilized on biocompatible or biomimetic electrode surfaces. Specifically, the article highlights new insights obtained by surface-enhanced resonance Raman (SERR), surface-enhanced infrared absorption (SEIRA), protein film infrared electrochemistry (PFIRE), polarization modulation infrared reflection-absorption spectroscopy (PMIRRAS), Förster resonance energy transfer (FRET), X-ray absorption spectroscopy (XAS), electron paramagnetic resonance (EPR), and differential electrochemical mass spectrometry (DMES)-based spectroelectrochemical methods on the structure, orientation, dynamics, and reaction mechanisms for a variety of immobilized species. This includes small heme and copper electron shuttling proteins, large respiratory complexes, hydrogenases, multicopper oxidases, alcohol dehydrogenases, endonucleases, NO-reductases, and dye decolorizing peroxidases, among other enzymes. Finally, I discuss the challenges and foreseeable future developments toward a better understanding of the functioning of these complex macromolecules and their exploitation in technological devices.Fil: Murgida, Daniel Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentin

Mapping biophysics through enhanced Monte Carlo techniques

This thesis is focused on the study of molecular interactions at the atomistic detail and is divided into one introductory chapter and four chapters referencing different problems and methodological approaches. All of them are focused on the development and improvement of computational Monte Carlo algorithms to study, in an efficient manner, the behavior of these systems at a classical molecular mechanics level. The four biophysical problems studied in this thesis are: induced fit docking between protein-ligand and between DNA-ligand to understand the binding mechanism, protein stretching response, and generation/ scoring of protein-protein docking poses. The thesis is organized as follows: First chapter corresponds to the state of the art in computational methods to study biophysical interactions, which is the starting point of this thesis. Our in-house PELE algorithm and the main standard methods such as molecular dynamics will be explained in detail. Chapter two is focused on the main PELE modifications to add new features, such as the addition of a new force field, implicit solvent and an anisotropic network specific for DNA simulation studies. We study, compare and validate the conformations generated by six representative DNA fragments with the new PELE features using molecular dynamics as a reference. Chapter three is devoted to applying the new methods implemented and tested in PELE to study protein-ligand interactions and DNA-ligand interactions using four systems. First, we study the porphyrin binding to Gun4 protein combining PELE and molecular dynamics simulations. Besides, we provide a docking pose that has been corroborated by a new crystal structure published during the revision process of the submitted study showing the accuracy of our predictions. In the second project, we use our improved version of PELE to generate the first structural model of an alpha glucose 1,6-bisphosphate substrate bound to the human Phosphomannomutase 2 demonstrating that this ligand can adopt two low-energy orientations. The third project is the study of DNA-ligand interactions for three cisplatin drugs where we evaluate the binding free energy using Markov state models. We show excellent results respect another free energy methods studied with molecular dynamics. The last project is the study of the daunomycin DNA intercalator where we simulate and study the binding process with PELE. Chapter four is focused on the computational study of force extension profiles during the protein unfolding. We added a dynamic harmonic constraint following a similar procedure applied in steered molecular dynamics to our Monte Carlo approach to fix or pull some selected atoms forcing the protein unfolding in a defined direction. We implement and compare with steered molecular dynamics this technique with Ubiquitin and Azurin proteins. Moreover, we add this feature to a well-known algorithm called MCPRO from William Jorgensen¿s group at YALE University to evaluate the free energy associated to the unfolding of the deca-alanine system. Chapter five corresponds to the introduction of a multiscale approach to study protein-protein docking. A coarse-grained model will be combined with a Monte Carlo exploration reducing the degrees of freedom to generate thousands of protein-protein poses in a quick way. Poses produced by this procedure will be refined and ranked through a protonation, hydrogen bond optimization, and minimization protocol at the all-atom representation to identify the best poses. I present two test cases where this procedure has been applied showing a good accuracy in the predictions: tryptogalinin and ferredoxin/flavodoxin systems.Aquesta tesi es centra en l'estudi de les interaccions moleculars amb detall atomic i es divideix en un capítol d'introducció i quatre capítols que fan referència a diferents problemes i enfocaments metodològics. Tots ells se centren en el desenvolupament i millora dels algoritmes computacionals de Monte Carlo per estudiar, de manera eficient, el comportament d'aquests sistemes a un nivell mecànica molecular clàssica. Els quatre problemes biofísics estudiats en aquesta tesi són: acoblament induït entre la proteïna-lligand i entre DNA-lligant per comprendre el mecanisme d'unió, resposta de les proteïnes a l'estirament, i la generació/puntuació d'acoblament entre poses proteïna-proteïna. La tesi s'organitza de la següent manera: El primer capítol correspon a l'estat de l'art en mètodes computacionals per estudiar les interaccions biofísiques, que és el punt de partida d'aquesta tesi. El nostre PELE algoritme i els principals mètodes estàndard com ara la dinàmica molecular s'explicaran en detall. El capítol dos es centra en les principals modificacions PELE per afegir noves característiques, com ara l'addició d'un nou camp de força, solvent implícit i modes normals per aquests estudis de simulació d'ADN. Es fa un estudi, comparació i validació de les conformacions generades per sis fragments d'ADN representatius amb PELE utilitzant dinàmica molecular com a referència. El tercer capítol està dedicat a l'aplicació dels nous mètodes implementats i provats en PELE per estudiar les interaccions proteïna-lligand i la interacció lligand-DNA utilitzant quatre sistemes. En primer lloc, se estudia la unió a proteïnes GUN4 combinant PELE i simulacions de dinàmica molecular. A més, es proposa un acoblament que ha sigut corroborat per una nova estructura cristal·lina publicada durant el procés de revisió de l'estudi mostrant l'exactitud de les nostres prediccions. En el segon projecte, hem utilitzat la nostra versió millorada de PELE per generar el primer model estructural d'una glucosa alfa substrat 1,6-bisfosfat unit a la fosfomanomutasa humana 2, que demostra que aquest lligant pot adoptar dues orientacions de baiza energia. El tercer projecte és l'estudi de les interaccions d'ADN lligant per tres medicaments cisplatí on se avalua l'energia lliure d'unió utilitzant Markov States Models. Es mostren excel·lents resultats respecte d'altres mètodes d'energia lliure estudiats amb dinàmica molecular. L'últim projecte és l'estudi de l'intercalador d'ADN anomenat daunomicina on es simula i estudia el procés d'unió amb PELE. El capítol 4 es centra en l'estudi computacional dels perfils d'extensió de la força durant el desplegament de la proteïna. Hem afegit una restricció harmònica dinàmica seguint un procediment similar al aplicat en dinàmica molecular en el nostre algoritme Monte Carlo per fixar o moure alguns àtoms seleccionats obligant a desplegar la proteïna en una direcció definida. Aquesta tècnica s'ha implementat i comparat amb dinàmica molecular per les proteïnes ubiquitina i azurin. D'altra banda, hem afegit aquesta modificació a un algoritme ben conegut anomenat MCPRO del grup de William Jorgensen a la Universitat de Yale per avaluar l'energia lliure associada al desplegament del sistema deca alanina. El capítol cinc correspon a la introducció d'un enfocament multiescala per estudiar l'acoblament proteïna-proteïna. Un model de gra gruixut es combinat amb una exploració Monte Carlo per reduir els graus de llibertat i generar milers de poses proteïna-proteïna d'una manera ràpida. Les poses produides per aquest procediment es perfeccionan i evaluan a través d'una protonació, optimització d'enllaços d'hidrogen, i minimització a escala atòmica per identificar les millors poses. Es presenten dos casos de prova on s'ha aplicat aquest procediment que mostra una bona precisió en les prediccions: tryptogalinin i ferredoxina / flavodoxina systems

Development of Polarizable Force Field Models for Transition Metal Ions

This dissertation focuses on the development of polarizable molecular mechanics (MM) force field models for the third-row transition metal (TM) ions. These TM ions perform important structural and chemical functions in a wide range of organic and biological environments because of the unique properties of the 3d orbitals. Being able study these systems in silico can provide a tremendous amount of information that is difficult to obtain through experiments. However, the standard treatment of ions in traditional MM models has shown to be insufficient for describing the d-shell electronic effects. In this work, empirical models for TM electronic effects are derived from the valence bond (VB) theory and the angular overlap model (AOM). The TM potential functions are incorporated into the AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) MM force field. A consistent polarizable electrostatics model is applied between metal and ligand sites at all interaction distance, enabling the study of ligand association / dissociation and other dynamic events. Specifically, theories are presented in the context of Ni(II), Cu(II) and Zn(II) ions. Parameters are obtained by fitting the TM models to gas-phase ab initio computations. Finally, results from molecular dynamics simulations of aqueous ions and select type 1 copper proteins (plastocyanin and azurin) are analyzed. Evidence from this study suggests that explicit description of d-shell electronic effect can significantly improve the performance of MM models. This allows one to perform more reliable investigations on complex TM systems than can be achieved with traditional MM methods but without the computational expense of ab initio calculations

The intersection of nuclear magnetic resonance and quantum chemistry

Nuclear Magnetic resonance and quantum chemistry have been recognized to be strong tools for probing the structure and dynamics of molecules to further solve chemistry and biological problems. Chemical shift measured by NMR experiment and chemical shielding, molecular energy and molecular structure calculated by quantum chemistry provide extensive information. Exact analytic gradients, are obtained for cavitation, dispersion and repulsion energies and time-dependent density functional theory for the continuum solvation model, which could be used to probe the structure, dynamics and properties of molecules. Copper in CuA azurin is recognized to be coordinated by a structure water molecule by comparing the experimental His120 pKa reported in literature with quantum mechanical calculation result. Accurate 13C NMR chemical shielding for small organic molecules can be obtained by quantum mechanical calculation by considering electron correlation effect, complete basis set extrapolation and vibrational correction. Basis set incompleteness is found to be the main source of inaccuracy and cannot be removed by applying any fixed correction, but is dependent on the chemical nature of the relevant group. The 13C chemical shielding of methyl, ethylene and ethyne carbon is significantly improved by vibrational correction. Trifluroacetic acid catalyzed retinoic acid isomerization is recognized to simultaneously decay to polymer by using 1H NMR method. Common intermediate occurs for the isomeration and all-trans, 9-cis and 9,13-dicis retinoic acid all first convert to 13-cis retinoic acid. Free energy changes obtained by NMR experiment compare well with the calculated result using quantum mechanical method done by Professor Harbison. Solid-State CPMAS NMR method shows that DL-aspartic acid crystalizes to racemic crystals rather than conglomerate over most of its temperature range, which is confirmed by PXRD. In contrast, glutamic acid crystalizes as a conglomerate under normal circumstances. Adviser: Gerard S. Harbiso