A signifficant obstacle facing the healthcare industry is the phenomenon of multidrug resistance (MDR) in which a cell acquires simultaneous resistance to many unrelated drugs that it has never been exposed to. At the molecular level, MDR can be characterised by a reduction of intracellular drug levels due to their active efflux by multidrug transporters such as P-glycoprotein (Pgp). Pgp is able to efflux a phenomenally wide variety of chemically unrelated drugs and causal relationships have been established between its expression and the acquisition of MDR to numerous anticancer and central nervous system (CNS) drugs. There has thus been much effort to understand the molecular biology of Pgp and how it functions. However, many aspects of its functioning remain unclear. From a drug discovery viewpoint, we have yet to fully understand what features make some drugs susceptible to Pgp-mediated efflux (substrates) and what makes others able to inhibit Pgp function (inhibitors). From a mechanistic viewpoint, it is still uncertain what the exact nature of Pgp's binding site is, the role of ATP binding and hydrolysis in transport and how both of these interplay with ligand binding. The work presented in this thesis attempts to answer these questions from two perspectives. Firstly the mouse Pgp crystal structure [PDB 3G60] was used as a unique starting point for molecular dynamics (MD) simulations to characterise the dynamics and conformational exibility of Pgp, properties believed to be integral to its function. The simulations revealed Pgp to be a highly dynamic molecule at both its transmembrane (TM) and nucleotide binding domains (NBDs). The latter exhibited a conformational asymmetry that supports the Constant Contact model of ATPase activity. In the presence of the Pgp substrate, daunorubicin, the NBDs exhibited tighter asymmetric dimerisation leading to increased affinity for ATP. In contrast, the presence of the Pgp inhibitor, QZ59-RRR led to NBD conformational changes that reduced their affinity for ATP. Thus providing an appealing mechanism for how QZ59-RRR inhibits Pgp ATPase activity. MD simulation was also used to provide atomic-detail interpretations of multiple binding stoichiometries of drug and lipid molecules observed by collaborator-led mass spectrometry experiments. This also provided opportunity to validate the Pgp simulations against novel experimental data. The second strand of the thesis explored the membrane permeation dynamics of CNS therapeutics in order to identify differences in protonation states, conformations, orientations and membrane localisation that might distinguish those that are Pgp substrates and from those that are not. These properties were studied using complementary MD simulation and nuclear magnetic resonance (NMR) techniques. The simulations revealed a novel set of criteria that in uence the likelihoodof a drug to 'flip-flop' across a membrane, a behaviour that may make drugs more susceptible to Pgp efflux. These observations were broadly consistent with the NMR experiments. However, the NMR data also highlighted limitations in the simulation approaches used in this thesis and emphasised the need to also consider the kinetics of permeation in addition to its thermodynamics.

Simulations of various hydration levels of lamellar phase 23:2 Diyne PC were performed, and subsequent, serial docking simulations of a tyrosine monomer were replicated for each system in both hydrated and dehydrated states.<br>The goal was to evaluate how hydration impacts self-assembly and crystallization on the surface, and<br>whether or not these simulations, when run sequentially, could determine the answer. It was discovered that hydrated and dehydrated surfaces behave differently, and that<br>headgroup orientation plays a role in the initial docking and self-assembly process of the tyrosine monomer. It was also determined that potential energy as a sole metric<br>for determining whether or not a specific conformation of intermolecular orientation is not entirely useful, and docking scores are likely useful metrics in discriminating between conformations with identical potential energy values. <br>

To design an efficient solar energy conversion device, theoretical input is extremely important to provide the basic guideline for experimental scientists, to fabricate the most efficient, cheap, and stable device with less efforts. This desire can be made possible if computational scientist use a proper theoretical protocol, design an energy material, then the experimentalist will only invest weeks or months on the synthetic effort. This thesis highlights my recent efforts in this direction. Monoclinic BiVO4 is has been using as a photocatalyst due to its stability, cheap, easily synthesizable, narrow band gap and ideal VB (-6.80 eV vs vacuum) but inappropriate CB (-4.56 eV vs vacuum) edge position, responsible for its low efficiency. We have carried out a comprehensive experimental and periodic density functional theory (DFT) simulations of the pristine, Oxygen defective (Ov), Se doped monoclinic BiVO4 and heterojunction with Selenium (Se-BiVO4), to improve not only its CB edge position but photocatalytic and charge carrier properties. It is found that Ov (1% Oxygen vacancy) and mild doped BiVO4 (1 to 2% Se) are thermodynamically stable, have ideal band edges ~ -4.30 eV), band gaps (~1.96 eV), and small effective masses of electrons and holes. We have also investigated the contribution of Se to higher performance by effecting morphology, light absorption and charge transfer properties in heterojunction. Finally, it is found that Se makes a direct Z-scheme (band alignments) with BiVO4 where the photoexcited electron of BiVO4 recombine with the VB of Se, consequences electron-hole separation at Se and BiVO4, respectively, as a result, enhanced photocurrent is obtained. Theoretical study of β-TaON in the form of primitive unit cell, supercell and its N, Ta, and O terminated surfaces are carried out with the help of periodic DFT. Optical and electronic properties of all these different species are simulated, which predict TaON as the best candidate for photocatalytic water splitting contrast to their Ta2O5 and Ta3N5 counterparts. The calculated bandgap, valence band, and conduction band edge positions predict that β-TaON should be an efficient photoanodic material. The valence band is made up of N 2p orbitals with a minor contribution from O 2p, while the conduction band is made up of Ta 5d. Turning to thin films, the valence band maximum; VBM (−6.4 eV vs. vacuum) and the conduction band minimum; CBM (−3.3 eV vs. vacuum) of (010)-O terminated surface are respectively well below and above the redox potentials of water as required for photocatalysis. Charge carriers have smaller effective masses than in the (001)-N terminated film (VBM −5.8 and CBM −3.7 eV vs. vacuum). However, due to wide band gap (3.0 eV) of (010)-O terminated surface, it cannot absorb visible wavelengths. On the other hand, the (001)-N terminated TaON thin film has a smaller band gap in the visible region (2.1 eV) but the bands are not aligned to the redox potential of water. Possibly a mixed phase material would produce an efficient photoanode for solar water splitting, where one phase performs the oxidation and the other reduction. Computational study of an optically transparent, near-infrared-absorbing low energy gap conjugated polymer, donor−acceptor−donor (D-A-D) with promising attributes for photovoltaic application is reported herein. The D and A moiety on the polymeric backbone have been found to be responsible for tuning the band gap, optical gap, open circuit (Voc) and short-circuit current density (Jsc) in the polymers solar cells (PSC). Reduction in the band gap, high charge transformation, and enhanced visible light absorption in the D-A-D system is because of strong overlapping of molecular orbitals of D and A. In addition, the enhanced planarity and weak steric hindrance between adjacent units of D-A-D, resulted in red-shifting of its onset of absorption. Finally, PSC properties of the designed D-A-D was modeled in the bulk heterojunction solar cell, which gives theoretical Voc of about 1.02 eV. DFT study has been carried out to design a new All-Solid-State dye-sensitized solar cell (SDSC), by applying a donor-acceptor conjugated polymer instead of liquid electrolyte. The typical redox mediator (I1−/I3−) is replaced with a narrow band gap, hole transporting material (HTM). A unique “upstairs” like band energy diagram is created by packing N3 between HTM and TiO2. Our theoretical simulations prove that the proposed configuration will be highly efficient as the HOMO level of HTM is 1.19 eV above the HOMO of sanitizer (dye); providing an efficient pathway for charge transfer. High short-circuit current density and power conversion efficiency is promised from the strong overlapping of molecular orbitals of HTM and sensitizer. A low reorganization energy of 0.21 eV and exciton binding energy of 0.55 eV, confirm the high efficiency of HTM. Theoretical and experimental studies of a series of four porphyrin-furan dyads were designed and synthesized, having anchoring groups, either at meso-phenyl or pyrrole-β position of a zinc porphyrin based on donor–π–acceptor (D–π–A) approach. The porphyrin macrocycle acts as donor, furan hetero cycle acts as π-spacer and either cyanoacetic acid or malonic acid group acts as acceptor. Optical bandgap, natural bonding, and molecular bonding orbital (HOMO–LUMO) analysis confirm the high efficiency pyrrole-β substituted zinc porphyrins contrast to meso-phenyl dyads. DFT study of polypyrrole-TiO2 composites has been carried out to explore their optical, electronic and charge transfer properties for the development of an efficient photocatalyst. Titanium dioxide (Ti16O32) was interacted with a range of pyrrole (Py) oligomers to predict the optimum composition of nPy-TiO2 composite with suitable band structure for efficient photocatalytic properties. The study has revealed that Py-Ti16O32 composites have narrow band gap and better visible light absorption capability compared to individual constituents. A red-shifting in λmax, narrowing band gap, and strong intermolecular interaction energy (-41 to −72 kcal/mol) of nPy-Ti16O32 composites confirm the existence of strong covalent type interactions. Electron−hole transferring phenomena are simulated with natural bonding orbital analysis where Py oligomers found as donor and Ti16O32 as an acceptor in nPy-Ti16O32 composites. Sensitivity and selectivity of polypyrrole (PPy) towards NH3, CO2 and CO have been studied at DFT. PPy oligomers are used both, in the doped (PPy+) and neutral (PPy) form, for their sensing abilities to realize the best state for gas sensing. Interaction energies and amount of charges (NBO and Mulliken charge analysis) are simulated which reveal the sensing ability of PPy towards these gases. PPy, both in doped and neutral state, is more sensitive to NH3 compared to CO2 and CO. More interestingly, NH3 causes doping of PPy and de-doping of PPy+, providing evidence that PPy/PPy+ is an excellent sensor for NH3 gas. UV-vis and UV-vis-near-IR spectra of nPy, nPy+, and nPy/nPy+-X complexes demonstrate strong interaction of PPy/PPy+ with these atmospheric gases. The applications of graphene (GR) and its derivatives in the field of composite materials for solar energy conversion, energy storage, environment purification and biosensor applications have been reviewed. The vast coverage of advancements in environmental applications of GR-based materials for photocatalytic degradation of organic pollutants, gas sensing and removal of heavy metal ions is presented. Additionally, the presences of graphene composites in the bio-sensing field have been also discussed in this review.

<div>Computational Chemistry has proven to be an effective means of solving chemical problems. The two main tools of Computational Chemistry - quantum mechanics and molecular mechanics, have provided viable avenues to probe such chemical problems at an electronic or molecular level, with varying levels of accuracy and speed. In this work, attempts have been made to combine the speed of molecular mechanics and the accuracy of quantum mechanics to work across multiples scales of time and length, effectively resulting in simulations of large chemical systems without compromising the accuracy.</div><div><br></div><div>The primary tool utilized for methods development and application in this work is the Effective Fragment Potential (EFP) method. The EFP method is a computational technique for studying non-covalent interactions in complex systems. EFP is an accurate \textit{ab initio} force field, with accuracy comparable to many Density Functional Theory (DFT) methods, at significantly lower computational cost. EFP decomposes intermolecular interactions into contributions from four terms: electrostatics, polarization, exchange-repulsion and dispersion.</div><div><br></div><div>In the first chapter, the possibility of applying EFP method to study large radical-water clusters is probed. An approximate theoretical model in which the transition dipole moments of excitations are computed using the information from the ground state orbitals is implemented.</div><div><br></div><div>A major challenge to broaden the scope of EFP is to overcome its limitation in describing only small and rigid molecules such as water, acetone, etc. In the second chapter, the extension of EFP method to large covalently bound biomolecules and polymers such as proteins, lipids etc., is described. Using this new method, referred to as BioEFP/mEFP, it is shown that the effect of polarization is non-negligible and must be accounted for when modeling photochemical and electron-transfer processes in photoactive proteins.</div><div><br></div><div>Another area of interest is the development of novel drug-target binding models, in which a chemically active part of the ligand is modified via functional group modification, while the rest of the system remains intact. In the third chapter, the development and application of a drug-target binding model is explained.<br></div><div><br></div><div><div>Lastly, in the fourth and final chapter, we show the derivation for working equations corresponding to the coupling gradient term describing the dispersion interactions between quantum mechanical and effective fragment potential regions.</div><div><br></div><div>The primary focus of this work is to explore and expand the boundaries of multiscale QM/MM simulations applied to chemical and biomolecular systems. We believe that the work described here leads to exciting pathways in the future in terms of modeling novel systems and processes such as heterogeneous catalysis, QSAR, crystal structure prediction, etc.</div></div>

<p>This thesis presents briefly the application of quantum mechanics on systems ofchemical interest, i.e., the field of quantum chemistry and computational chemistry.The molecules of the ten-electron series, hydrogen fluoride, water, ammonia,methane and neon, are taken as computational examples. Some applications ofquantum chemistry are then shown on these systems, with emphasis on the natureof the molecular bonds. Conceptual methods of chemistry and theoreticalchemistry for these systems are shown to be valid with some restrictions, as theseinterpretations does not represent physically measurable entities.The orbitals and orbital energies of neon is studied, the binding van der Waalsinteractionresulting in a Ne2 molecule is studied with a theoretical bond lengthof 3.23 °A and dissociation energy of 81.75 μEh. The equilibrium geometries ofFH, H2O, NH3 and CH4 are studied and the strength and character of the bondsinvolved evaluated using bond order, dipole moment, Mulliken population analysisand L¨owdin population analysis. The concept of electronegativity is studied in thecontext of electron transfer. Lastly, the barrier of inversion for NH3 is studied, withan obtained barrier height of 8.46 mEh and relatively constant electron transfer.</p>

The main focus of this thesis is on the aromaticity of the ground state and electronically excited states of π-conjugated molecules and polymers, as well as how aromaticity is connected to their properties. The electronic structures of polybenzenoid hydrocarbons (PBHs) were explored through density functional theory (DFT) calculations and the π-component of the electron localization function (ELFπ). The study revealed how the π-electronic structure is influenced by the fusion of double bonds or benzene rings to the PBHs. We also demonstrated that the π-electrons of benzene extend to accommodate as much aromaticity as possible when bond length distorted.   The aromatic chameleon property displayed by fulvenes, isobenzofulvenes, fulvalenes, bis(fulvene)s, and polyfulvenes were investigated using DFT calculations. The tria-, penta-, and heptafulvenes were shown to possess ionization energies and electron affinities which can be tuned extensively by substitution, some of which even outperform TTF and TCNQ, the prototypical electron donor and acceptor, respectively. The singlet-triplet energy gap of pentafulvenes can be tuned extensively by substitution to the point that the triplet state is lower than the singlet state and thus becomes the ground state. The ELFπ of isobenzofulvene shows that the benzene ring in an electronically excited state can be more aromatic than the corresponding ring in the ground state. We have shown that the 6-ring of [5.6.7]quinarene is influenced by a Hückel aromatic resonance structure with 4n+2 π-electrons in the excited quintet state. The bis(fulvene)s which are composed of a donor type heptafulvene and an acceptor type pentafulvene, retain the basic donor-acceptor properties of the two fragments and could function as compact donor-acceptor dyads. A few of the designed polyfulvenes were found to have band gaps below 1 eV at the PBC-B3LYP/6-31G(d) level. Various 2,7-disubstituted fluorenones and dibenzofulvenes were synthesized and their excited state properties were investigated by absorption spectroscopy and time-dependent DFT calculations. It was found that the 1A → 1B transition of ππ* character can be tuned by substitution in the 2,7-positions. The 2,7-bis(N,N-dimethyl) derivatives of fluorenone and dibenzofulvene displayed low energy transitions at 2.18 and 1.61 eV, respectively, in toluene.

This thesis presents briefly the application of quantum mechanics on systems ofchemical interest, i.e., the field of quantum chemistry and computational chemistry.The molecules of the ten-electron series, hydrogen fluoride, water, ammonia,methane and neon, are taken as computational examples. Some applications ofquantum chemistry are then shown on these systems, with emphasis on the natureof the molecular bonds. Conceptual methods of chemistry and theoreticalchemistry for these systems are shown to be valid with some restrictions, as theseinterpretations does not represent physically measurable entities.The orbitals and orbital energies of neon is studied, the binding van der Waalsinteractionresulting in a Ne2 molecule is studied with a theoretical bond lengthof 3.23 °A and dissociation energy of 81.75 μEh. The equilibrium geometries ofFH, H2O, NH3 and CH4 are studied and the strength and character of the bondsinvolved evaluated using bond order, dipole moment, Mulliken population analysisand L¨owdin population analysis. The concept of electronegativity is studied in thecontext of electron transfer. Lastly, the barrier of inversion for NH3 is studied, withan obtained barrier height of 8.46 mEh and relatively constant electron transfer.

Des del descobriment del buckminster ful.lerè el 1985, s'ha despertat un interés enorme per entendre la reactivitat química així com les propietats d'aquests compostos. La funcionalització exoèdrica del ful.lerè més abundant, el C60, està força ben establerta. Tanmateix, la investigació en aquest camp encara continua oberta ja que s'han sintetitzat una gran varietat de derivats molt prometedors donades les seves futures aplicacions. La tesi comprèn quinze capítols que contenen set publicacions relacionades. Els primers dos estudis es basen en la reacció Diels-Alder sobre els anomenats metal.loful.lerens endoèdrics TNT X3N@C78, X= Sc, Y. Aquest projecte de investigació està motivat pel desconeixament existent sobre les possibles conseqüències de l'encapsulació del grup X3N. El tercer estudi descriu minuciosament els canvis detectats en la funcionalització exoèdrica un cop s'ha produït l'encapsulació dels diferents gasos nobles. En aquesta tesi s'estudia en detall l'ús de l'aproximació ONIOM per a estudiar reaccions de cicloaddició en compostos ful.lerènics. Els resultats d'aquest projecte són d'alt interès per a la realització dels estudis posteriors sobre la reacció de Diels-Alder i la 1,3-dipolar en ful.lerens i derivats. Finalment, l'última part d'aquesta tesi es basa en les propietats antioxidants de determinats ful.lerens. A l'últim treball inclòs en aquesta tesi s'estudia en detall el mecanismo de reacció per a la eliminació del ió superòxid en presència de ful.lerens. / Since the buckminster fullerene discovery in 1985, a huge interest for understanding the chemical reactivity as well as the chemical properties of fullerene compounds has been awakened. The exohedral functionalization of the archetypal compound C60 is nowadays considered to be quite well-established. Still, the research in this field is open as a wide variety of derivatives with intriguing potential applications have been synthesized. The thesis is divided into fifteen chapters that contain seven related publications. The first two studies are based on the Diels-Alder reaction involving the Trimetallic Nitride Template (TNT) endohedral metallofullerenes X3N@C78, X = Sc, Y . This investigation project was basically motivated by the unclear evidence about the possible consequences of the X3N. The third study thoroughly describes the change on the exohedral functionalization upon noble gas encapsulation. In the fourth study included in this thesis, the performance of the ONIOM approach for studying cycloaddition reactions involving fullerene compounds is studied in detail. Results from the latter project are of interest for the following studies involving the 1,3-dipolar and the Diels-Alder cycloaddition reactions where the ONIOM strategy is employed. Finally, the last part of this thesis is based on the antioxidant properties of fullerene compounds, where the mechanism of action for the superoxide removal involving fullerene compounds is unraveled. The understanding of the SOD removal mechanism could represent a big improvement to design new fullerene derivatives with higher antioxidant properties.

Des del seu descobriment, a la molècula C60 se li coneixen una varietat de derivats segons el tipus de funcionalització amb propietats fisicoquímiques específiques de gran interès científic. Una sel·lecció de derivats corresponents a addicions simple o múltiple al C60 s'ha considerat en aquest treball d'investigació. L'estudi a nivell de química computacional de diversos tipus d'addició al C60 s'han portat a terme per tal de poder donar resposta a aspectes que experimentalment no s'entenen o són poc clars.Els sistemes estudiats en referència a l'addició simple al C60 han estat en primer lloc els monoiminoful·lerens, C60NR, (de les dues vies proposades per la seva síntesi, anàlisis cinètic i termodinàmic han ajudat a explicar els mecanismes de formació i justificar l'addició a enllaços tipus [5,6]), i en segon lloc els metanoful·lerens i els hidroful·lerens substituits, C60CHR i C60HR, (raons geomètriques, electròniques, energètiques i magnètiques justifiquen el diferent caràcter àcid ente ambdós derivats tenint en compte una sèrie de substituents R amb diferent caràcter electrònic donor/acceptor). Els fluoroful·lerens, C60Fn, i els epoxid ful·lerens, C60On, (anàlisi sistemàtic dels seus patrons d'addició en base a poder justificar la força que els governa han aportat dades complementàries a les poques que existeixen experimentalment al respecte). / Since the discovery of C60 molecule a large number of derivatives molecules have been described with a great scientific interest of their specific physical and chemical properties. A selection of single and multiple addition products has been considered in this investigation. Study at Computational Chemistry level for this selected derivatives have been carried out in order to give answer to several points that experimentally are not understandable or not enough clear.As single addition derivatives, firstly were studied the monoiminofullerenes, C60NR, (two routes of synthesis have been considered, kinetic and thermodynamic analysis have help to explain formation mechanisms and justify the possible addition at [5,6]-type bonds), and secondly the methanofullerenes and the substituted hydrofullerenes, C60CHR and C60HR, (geometric, electronic, energetic and magnetic reasons justify the different acid character between both series of derivatives taking care on the influence of R substituents with different donor/acceptor character). The fluorofullerenes, C60Fn, and the epoxide fullerenes, C60On, have been studied as multiple addition derivatives (systematic analysis of the addition pattern have been performed in the way to find reasons to justify the driving force of the multiple addition process).

In this thesis, six small molecules (S-allylcysteine, S-allyl mercaptocysteine, allicin, methyl propyl disulfide, allyl methyl sulfide and dipropylsulfide) that are found in garlic and onion, and are known to be beneficial for human health were studied using molecular mechanics, semi-empirical methods, ab-initio (Restricted Hartree Fock), and density functional theory. Using the same methods, a synthetic pyrethroid pesticide molecule, called cyfluthrin, was also studied. Structural, vibrational and electronic properties of these molecules were found. These theoretical studies could clarify the role of these molecules on human health before they are commercially developed and used. In addition, unfolding dynamics of small peptide sequences (DDATKTFT and its variants) in immunoglobulin G-binding protein G was investigated. Protein folding and unfolding is one of the most important unsolved problems in molecular biology. Because of the large number of atoms involved in protein folding, it is a massive computational problem. The hope is that, one could understand this mechanism with the help of molecular dynamics simulation on small peptides. One of our findings is that the location of the hydrogen bonds is important for the stability of the peptide.