Evaluación teórica de las propiedades electrónicas y estructurales que afectan a la conductividad eléctrica en copolímeros de furano-tiofeno / Theoretical evaluation of the electronic and structural properties that affect the electrical conductivity in furan-thiophene copolymers / Avaliação teórica das propriedades eletrônicas e estruturais que afetam à condutividade eléctrica em copolímeros de furano-tiofeno

Resumen Desde el punto de vista científico y tecnológico ha habido un gran interés en el uso de monosustituyentes de furano y tiofeno como polímeros conductores, debido a sus múltiples aplicaciones como OLED, amplificadores ópticos, nanotecnología, entre otros. Por ello, el propósito de este trabajo fue estudiar los aspectos teóricos que afectan las propiedades electroconductoras de este tipo de moléculas. Se determinaron teóricamente los aspectos estructurales y electrónicos que influyeron en la conductividad de copolímeros de furano-tiofeno monosustituidos, al utilizar grupos carboxilos, metilos, hidroxilos, ciano y fluoruros como sustituyentes en el carbono C3 y C10 de cada heterociclo. La diferencia de energía entre el LUMO y el HOMO (band gap, Eg) y el potencial de ionización (PI) fue calculada a partir de las geometrías optimizadas en DFT para el estado neutro, anión y catión. Los PI y la Eg de los copolímeros fueron obtenidos mediante la extrapolación de los valores del oligómero a (1/N) y de una cadena de longitud infinita (1/N=0), obteniéndose una correlación lineal (R=0,99), la cual se mantiene a lo largo de todos los modelos de ajuste de cada copolímero analizado en el estudio.

Abstract There has been great scientific and technological interest in the use of mono-substituents of furan and thiophene as conducting polymers due to their multiple applications such as OLED, optical amplifiers and nanotechnology, among others. For this, the purpose of this work was to study the theoretical aspects that affect the electroconductive properties of this type of molecules. The structural and electronic properties that influence the conductivity of mono substituted-furan-thiophene copolymers were determined theoretically. The effect of using carboxyl, methyl, hydroxyl, cyano, and fluoride groups as substituents on the carbon C3 and C10 of each heterocycle was observed. The energy difference between the LUMO and the HOMO (band gap, Eg) and the ionization potential (IP) were calculated from the geometries optimized in DFT for the neutral, anion and cation state. The PI and Eg of the copolymers were obtained by extrapolating the values of the oligomer a (1/N) and a chain of infinite length (1/N=0) for which a linear correlation was obtained (R=0.99). This correlation is maintained throughout all the adjustment models of each copolymer analyzed in the study.

Resumo Existe muito interesse os termos científicos e tecnológicos em utilizar substituintes mono-substituídos furano e tiofeno como polímeros condutores devido às suas múltiplas aplicações, tais como OLED, amplificadores ópticos e nanotecnologia, entre outros. O objetivo deste trabalho foi estudar os aspectos teóricos que afetam as propriedades eletrocondutoras deste tipo de moléculas. Neste contribuição os aspectos estruturais e electrónicas que influenciam a condutividade de copolímeros furano-tiofeno substituos mono teoricamente determinada observando o efeito do uso de grupos carboxilo, metilo, hidroxilo, ciano e fluoretos como substituintes em C3 e C10 de carbono de cada heterociclo. A diferença de energia entre o LUMO e o HOMO (intervalo de banda, Eg) e o potencial de ionização (IP) foram calculadas a partir das geometrias optimizadas de DFT para o estado neutro, anião e catião. O PI e o Eg dos copolímeros foram obtidos por extrapolação dos valores do oligómero (1/N) e extrapolando para uma cadeia de comprimento infinito (1/ N=0) para os quais uma correlação linear foi obtida (R=0,99), que é mantido ao longo de todos os modelos de ajuste de cada copolímero analisados no estudo.

Population density analysis for determining the protonation state of the catalytic dyad in BACE1-tertiary carbinamine-based inhibitor complex.

BACE1 is an aspartyl protease with a very relevant role in medicinal chemistry related to Alzheimer Disease since it has demonstrated to be a promising therapeutic target for inhibition and possible control for the progress of the peptide accumulation characteristic of this pathology. The enzymatic activity of this protein is given by the aspartic dyad, Asp93 and Asp289, which can adopt several protonation states depending on the chemical nature of its inhibitors, this is, monoprotonated, diprotonated and di-deprotonated states. In the present study, the analysis of the population density, for a series of protein-inhibitor molecular dynamics simulations, was carried out to identify the most feasible protonation state adopted by the catalytic dyad in the presence of tertiary carbinamine (TC) transition state analog inhibitors. The results revealed that the monoprotonated Asp289i state, in which the Asp93 and Asp289 residue side chains are deprotonated and protonated on the inner oxygen, respectively, is the most preferred in the presence of TC family inhibitors. This result was obtained after evaluating, for all 9 possible protonation state configurations, the individual and combined population densities of a set of parameters sensitive to protonation state of the Aspartic dyad, using an X-ray experimental BACE1/TC crystallographic structure as reference. This case study demonstrates again the usefulness of the concept of population density as a quantitative tool to establish the most stable system settings, among all possible, by measuring the level of occurrence of simultaneous events obtained from a sampling over time. These results will help to clear the phenomena related to the TCs inhibitory pathway, as well as assist in the design of better TC inhibitors against Alzheimer's protease.

A molecular dynamics study of the BACE1 conformational change from Apo to closed form induced by hydroxyethylamine derived compounds.

BACE1 is an aspartyl protease which is a therapeutic target for Alzheimer's disease (AD) because of its participation in the rate-limiting step in the production of Aß-peptide, the accumulation of which produces senile plaques and, in turn, the neurodegenerative effects associated with AD. The active site of this protease is composed in part by two aspartic residues (Asp93 and Asp289). Additionally, the catalytic site has been found to be covered by an antiparallel hairpin loop called the flap. The dynamics of this flap are fundamental to the catalytic function of the enzyme. When BACE1 is inactive (Apo), the flap adopts an open conformation, allowing a substrate or inhibitor to access the active site. Subsequent interaction with the ligand induces flap closure and the stabilization of the macromolecular complex. Further, the protonation state of the aspartic dyad is affected by the chemical nature of the species entering the active site, so that appropriate selection of protonation states for the ligand and the catalytic residues will permit the elucidation of the inhibitory pathway for BACE1. In the present study, comparative analysis of different combinations of protonation states for the BACE1-hydroxyethylamine (HEA) system is reported. HEAs are potent inhibitors of BACE1 with favorable pharmacological and kinetic properties, as well as oral bioavailability. The results of Molecular Dynamics (MD) simulations and population density calculations using 8 different parameters demonstrate that the LnAsp289 configuration (HEA with a neutral amine and the Asp289 residue protonated) is the only one which permits the expected conformational change in BACE1, from apo to closed form, after flap closure. Additionally, differences in their capacities to establish and maintain interactions with residues such as Asp93, Gly95, Thr133, Asp289, Gly291, and Asn294 during this step allow differentiation among the inhibitory activities of the HEAs. The results and methodology here reported will serve to elucidate the inhibitory pathway of other families of compounds that act as BACE1 inhibitors, as well as the design of better leader compounds for the treatment of AD.

Determination of the protonation state for the catalytic dyad in ß-secretase when bound to hydroxyethylamine transition state analogue inhibitors: A molecular dynamics simulation study.

BACE1 is an aspartyl protease of pharmacological interest for its direct participation in Alzheimer's disease (AD) through ß-amyloid peptide production. Two aspartic acid residues are present in the BACE1 catalytic region which can adopt multiple protonation states depending on the chemical nature of its inhibitors, i.e., monoprotonated, diprotonated and di-deprotonated states. In the present study a series of protein-ligand molecular dynamics (MD) simulations was carried out to identify the most feasible protonation state adopted by the catalytic dyad in the presence of hydroxyethylamine transition state analogue inhibitors. The MD trajectories revealed that the di-deprotonated state is most prefered in the presence of hydroxyethilamine (HEA) family inhibitors. This appears as a result after evaluating, for all 9 protonation state configurations during the simulation time, the deviations of a set of distances and dihedral angles measured on the ligand, protein and protein-ligand complex with reference to an X-ray experimental BACE1/HEA crystallographic structure. These results will help to clarify the phenomena related to the HEAs inhibitory pathway, and improve HEAs databases' virtual screening and ligand design processes targeting ß-secretase protein.