RESUMO

La proteína proteasa 3CLpro del SARS-CoV-2 es una enzima crucial para la replicación viral, razón por la cual se convierte en un blanco terapéutico de gran importancia. El timol (2-isopropil-5-me-tilfenol), un compuesto natural que se encuentra en el tomillo (Thymus vulgaris), exhibe potencial actividad antiviral contra la proteasa 3CLpro. En este estudio, usando acoplamiento molecular con AutoDockTools-1.5.6, se evaluaron las energías de interacción molecular entre el timol y los residuos de aminoácidos en el sitio activo de la proteína proteasa 3CLpro. Luego, con la teoría cuántica de Átomos en Moléculas (QTAIM) y la de Interacciones no covalentes (NCI) se analizaron los tipos de interacciones moleculares entre los residuos de aminoácidos identificados y el timol. Los cálculos cuánticos se llevaron con el software Orca-5.0.3, utilizando el método DFT con el funcional M06-2X y el conjunto base aug-cc-pVDZ en fase gaseosa. Los resultados de acoplamiento molecular indican que el timol se une a la proteína 3CL con una energía de interacción igual a -3,784 kcal/mol. El análisis QTAIM indica la presencia de puntos críticos de enlace entre el timol y los residuos HIS41 y CYS145. Además, se observa la formación de un enlace de hidrógeno entre el grupo OH del timol y el residuo CYS145, lo cual es corroborado por los análisis ELF (Electron Localization Function) y NCI (Non Covalent Interactions). Finalmente, el método NCI confirma la presencia de interacciones de Van der Waals con el residuo HIS41. Los resultados sugieren que el mecanismo de inhibición de la actividad de la proteína 3CLpro es controlado por interacciones moleculares tipo puente de hidrógeno e interacciones débiles.

The protease 3CLpro of the SARS-CoV-2 is a crucial enzyme for viral replication, becoming a highly important therapeutic target. Thymol (2-isopropyl-5-methyl-phenol), a naturally occurring compound found in thyme, exhibits potential antiviral activity against the 3CLpro protease. In this study, using molecular docking with AutoDockTools-1.5.6, the molecular interaction energies between thymol and amino acid residues in the active site of the protein protease 3CLpro were evaluated. Then, with the Atoms in Molecules (QTAIM) and Non-covalent Interactions (NCI) theories, the types of molecular interactions between identified amino acid residues and thymol were analyzed. Quantum calculations were carried out with the Orca-5.0.3 software using the DFT method with the M06-2X functional and the aug-cc-pVDZ basis set in the gas phase. The molecular docking results indicate that thymol is linked to the 3CL protein with an interaction energy equal to -3.784 kcal/mol. QTAIM analysis indicates the presence of critical binding sites between thymol and residues HIS41 and CYS145. In addition, the formation of a hydrogen bond between the OH group of thymol and the CYS145 residue is observed, which is corroborated by the ELF and NCI analyses. Finally, the NCI method confirms the presence of Van der Waals interactions with the HIS41 residue. The results suggest that the mechanism of inhibition of the activity of the 3CLpro protein is controlled by molecular interactions such as hydrogen bonding and weak interactions.

A protease 3CLpro do SARS-CoV-2 é uma enzima crucial para a replicação viral, tornando-se um alvo terapêutico de grande importÅncia. O timol (2-isopropil-5-me-tilfenol), um composto natural encontrado no tomilho, exibe potencial atividade antiviral contra a protease 3CLpro. Neste estudo, utilizando o docking molecular com o AutoDockTools-1.5.6, foram avaliadas as energias de interação molecular entre o timol e os residuos de aminoácidos no sítio ativo da proteína protease 3CLpro. Em seguida, com a teoria quantica de atomos em moleculas (QTAIM) e da interacões no-covalentes (NCI), foram analisados os tipos de interações moleculares entre os resíduos de aminoácidos identificados e o timol. Os cálculos quÅnticos foram realizados com o software Orca-5.0.3 usando o método DFT com o funcional M06-2X e a base aug-cc-pVDZ definida na fase gasosa. Os resultados do docking molecular indicam que o ti-mol está ligado à proteína 3CL com uma energia de interação igual a -3.784 kcal/ mol. A análise QTAIM indica a presença de sítios de ligação críticos entre o timol e os resíduos HIS41 e CYS145. Além disso, observa-se a formação de uma ponte de hidrogênio entre o grupo OH do timol e o resíduo CYS145, o que é corroborado pelas análises ELF e NCI. Finalmente, o método NCI confirma a presença das interações de Van der Waals com o resíduo HIS41. Os resultados sugerem que o mecanismo de inibição da atividade da proteína 3CLpro é controlado por interações moleculares como ligações de hidrogênio e interações fracas.

RESUMO

El comportamiento molecular de la amoxicilina en agua fue explorado con solvatación implícita y explícita mediante dos estrategias que combinan diferentes técnicas de simulación molecular para evaluar el alcance de estos procedimientos. Con estas dos estrategias de cálculo computacional, la conformación molecular de la amoxicilina fue determinada en fase acuosa. En la primera estrategia se utilizó el generador de conformaciones Ballon-v1.8.2 y la estabilidad de las conformaciones en agua fue evaluada utilizando la energía libre de solvatación determinada con el método de solvatación implícita SMD. En la segunda estrategia, con la dinámica molecular tipo NVT fue evaluado el arreglo espacial de esta molécula en agua y, además, la interacción molecular entre la amoxicilina y el agua fue evaluada en esta simulación. Los resultados obtenidos muestran que la conformación de la amoxicilina más estable en fase acuosa es la plegada. Además, los valores de energías de solvatación de -121,42 y -14,58 kJ/mol obtenidos con solvatación implícita y dinámica molecular sugieren que esta molécula tiene una alta afinidad por el agua. Las funciones distribución radial y espacial sugieren que se forman 3 capas de solvatación alrededor de la amoxicilina y que esta molécula tiene una región altamente hidrofílica. Finalmente, la estrategia usando dinámica molecular permite obtener mejores conformaciones en equilibrio que la estrategia de simulación usando el generador de conformaciones Ballon-v1.8.2.

The molecular behavior of amoxicillin in water was explored with implicit and explicit solvation using two strategies that combine different molecular simulation techniques to assess the scope of these procedures. With these two computational calculation strategies, the molecular conformation of amoxicillin was determined in aqueous phase. In the first strategy, the conformation generator Ballon-v1.8.2 was used and the stability of the conformations in water was evaluated using the solvation free energy determined with the SMD implicit solvation method. In the second strategy, with NVT-type molecular dynamics, the spatial arrangement of this molecule in water was evaluated and, in addition, the molecular interaction between amoxicillin and water was evaluated in this simulation. The results obtained show that the most stable conformation of amoxicillin in the aqueous phase is the folded one. In addition, the solvation energy values of -121.42 and -14.58 kJ/mol obtained with implicit solvation and molecular dynamics suggest that this molecule has a high affinity for water. The radial and spatial distribution functions suggest that 3 solvation shells form around amoxicillin and that this molecule has a highly hydrophilic region. Finally, the strategy using molecular dynamics allows to obtain better equilibrium conformations than the simulation strategy using the Ballon-v1.8.2 conformation generator.

O comportamento da amoxicilina em água foi analisado com solvatação implícita e explícita mediante duas estratégias que combinam diferentes técnicas de simulação molecular para avaliar o escopo destes procedimentos. Com estas duas estratégias de cálculo computacional, a conformação molecular da amoxicilina foi determinada em fase aquosa. Na primeira estratégia, utilizou-se o gerador de conformação do software Ballon-v1.8.2 e avaliou-se a estabilidade das conformações em água a partir da energia livre de solvatação determinada pelo método de solvatação implícita SMD. Na segunda estratégia, avaliou-se o arranjo espacial da amoxicilina e sua interação com a água através de simulações de dinâmica molecular NVT. Os resultados obtidos mostram que a conformação dobrada é a mais estável em fase aquosa. Ademais, os valores de energía de solvatação de -121,42 e -14,58 kJ/mol obtidos com solvatação implícita e dinâmica molecular sugerem que esta molécula possui alta afinidade pela água. As funções de distribuição radial e espacial sugerem que se formam 3 camadas de solvatação ao redor da amoxicilina e que esta molécula possui uma região altamente hidrofílica. Finalmente, a estratégia usando dinâmica molecular permite obter melhores conformações de equilíbrio do que a estratégia de simulação usando o gerador de conformação do software Ballon-v1.8.2.

RESUMO

The nature of the interaction between the molecules of the sodium dodecyl sulfate surfactant forming two crystal phases, one anhydrous, NaC12H25O4S and the other, NaC12H25O4S.H2O, hydrated with one water molecule for unit cell, has been studied in detail using the quantum theory of atoms in molecules and a localized electron detector function. It was found that for the anhydrous crystal, the head groups of the surfactant molecules are linked into a head-to-head pattern, by a bond path network of Na-O ionic bonds, where each Na+ atom is attached to four S O 4 - groups. For the hydrated crystal, in addition to these four bonds for Na+, two additional ones appear with the oxygen atoms of the water molecules, forming a bond paths network of ionic Na-O bonds, that link the Na+ atoms with the S O 4 - groups and the H2O molecules. Each H2O molecule is bonded to two S O 4 - groups via hydrogen bonds, while the S O 4 - groups are linked to a maximum of four Na+ atoms. The phenomenon of aggregation of the sodium dodecyl sulfate molecules at the liquid water/vacuum interface was studied using NVT molecular dynamics simulations. We have found that for surfactant aggregates, the Na+ ions are linked to a maximum of three SO4 - groups and three water molecules that form Na-O bonds. Unlike hydrated crystal, each of the O atoms that make these Na-O bonds is linked to only one Na+ ion. Despite these differences, like the crystal phases, the surfactant molecules tend to form a head-to-head network pattern of ionic Na-O bonds that link their heads. The present results indicate that the clustering of anionic surfactant at the water/vacuum interface is a consequence of the electrostatic alignment of the cationic and anionic groups as occurs in the crystalline phases of sodium dodecyl sulfate.

RESUMO

The solubility parameters, δ, of several asphaltene models were calculated by mean of an atomistic NPT ensemble. Continental and archipelago models were explored. A relationship between the solubility parameter and the molecule structure was determined. In general, increase of the fused-rings number forming the aromatic core and the numbers of heteroatoms such as oxygen, nitrogen, and sulfur produces an increase of the solubility parameter, while increases of the numbers and length of the aliphatic chains yield a systematic decrease of this parameter. Molecules with large total carbon atom number at the tails, n(c), and small aromatic ring number, n(r), exhibit the biggest values of δ, while molecules with small n(c) and large n(r) show the smallest δ values. A good polynomial correlation δ = 5.967(n(r)/n(c)) - 3.062(n(r)/n(c))(2) + 0.507(n(r)/n(c))(3) + 16.593 with R(2) = 0.965 was found. The solubilities of the asphaltene models in toluene, heptane, and amphiphiles were studied using the Scatchard-Hildebrand and the Hansen sphere methodologies. Generally, there is a large affinity between the archipelago model and amphiphiles containing large aliphatic tails and no aromatic rings, while continental models show high affinity for amphiphiles containing an aromatic ring and small aliphatic chains.