O PIBID na formação inicial docente: como superar a distância física da sala de aula e manter a essência do Programa / PIBID in initial teacher training: how to overcome the physical distance from the classroom and keep the essence of the Program

Neste trabalho, apresentamos as experiências mais marcantes vivenciadas por um grupo de alunos do curso de Licenciatura em Matemática do Instituto Federal Catarinense, Campus de Camboriú, que participam do Programa Institucional de Bolsas de Iniciação à Docência (Pibid), o qual antecipa o vínculo entre os acadêmicos e a prática docente. Os objetivos específicos das atividades realizadas foram desenvolver e aprimorar a leitura, a escrita e a oratória de todos os envolvidos, bem como se apropriar da Base Nacional Comum Curricular (BNCC). As experiências foram desenvolvidas no período 10/2020 a 07/2021, mediante encontros remotos, não sendo possível desenvolver ações nos diferentes espaços físicos escolares ou outros espaços formativos. Mesmo assim, com toda a comunidade escolar “confinada” no ambiente virtual, por conta da COVID-19, tivemos um ganho substancial a partir dos obstáculos enfrentados. Realizamos diferentes procedimentos metodológicos: rodada de leitura e discussão de artigos; reuniões do Núcleo Local do Pibid e com o Subprojeto Interdisciplinar;  acompanhamento de aulas síncronas, aulas remotas e atividades propostas no Google Classroom; observação, acompanhamento e discussão de Experimentos do Estágio Supervisionado Obrigatório, apresentado por concluintes do curso; leitura da BNCC seguida do desenvolvimento de trabalhos sobre o documento, especificamente da Matemática, e posterior socialização e discussão com colegas da Física e Matemática do Campus de Rio do Sul. Produção de “memórias das reuniões”. Como resultados, observamos que o contato com artigos e bibliografias de autores tradicionais ou contemporâneos, estudos dirigidos à formação de professores que ensinam Matemática, participação em eventos online etc. possibilitaram, além do contato com quem leciona, o aperfeiçoamento de habilidades como escrita, oratória, expressão, desinibição e desenvoltura. A experiência foi tão promissora que resultou na criação de uma oficina de Probabilidade e Estatística com interdisciplinaridade, para anos iniciais do Ensino Fundamental, ministrada para turma da Residência Pedagógica do curso de Pedagogia do campus de Camboriú, desmistificando a Matemática e proporcionando uma aproximação entre as licenciaturas de Pedagogia e de Matemática. O acompanhamento de aulas e atividades permitiu-nos perceber e observar as distintas “didáticas” e como cada Professor, utilizando recursos tecnológicos, como mesa digital, software Geogebra, aulas gravadas, etc., busca ganhar a atenção de seus alunos. A observação e o acompanhamento da apresentação dos Experimentos do Estágio Supervisionado Obrigatório, além da socialização desses estágios, foram momentos únicos de aprendizagem sem precedentes. A adoção de “memórias” das reuniões no lugar de atas foi positivamente avaliada. Nas descrições e narrativas de livre escolha, cada Pibidiano trouxe relatos com enorme riqueza de detalhes. Enfim, os conhecimentos são construídos conforme nos adaptamos aos desafios impostos e, à vista da pandemia vivenciada, adequamo-nos da melhor maneira possível. No ensino remoto emergencial, a inovação, a criatividade, a inventividade, a articulação entre a teoria e a prática contribuem para o desenvolvimento da autonomia de alunos de Iniciação à Docência

Revisiting Partition in Hydrated Bilayer Systems

We discuss potential-of-mean force convergence issues involving the methods for generating starting structures of umbrella sampling simulations for the study of the water–bilayer permeation of drug-like compounds. We provide a proof of concept of the benefits of potential-energy modification methods, in particular the flooding technique, to enhance the sampling and improve the convergence of the potential-of-mean force. In addition, we also discuss how these potential modifiers could introduce the necessary bias to induce the correct description of other relevant internal degrees of freedom for the compounds, thus providing a more accurate description of the permeation process. Effective methodological approximations are taken into consideration, more specifically the inclusion of atomic polarization, and experimental data are used in the validation of computed values whenever possible. The parametrization of the atomic point charges is always a relevant issue in biomolecular simulations. We discuss the influence of a molecule’s conformation-dependent atomic point charges and their impact on the predicted potential-of-mean force

AutoDock4_Zn: An Improved AutoDock Force Field for Small-Molecule Docking to Zinc Metalloproteins

Zinc is present in a wide variety of proteins and is important in the metabolism of most organisms. Zinc metalloenzymes are therapeutically relevant targets in diseases such as cancer, heart disease, bacterial infection, and Alzheimer’s disease. In most cases a drug molecule targeting such enzymes establishes an interaction that coordinates with the zinc ion. Thus, accurate prediction of the interaction of ligands with zinc is an important aspect of computational docking and virtual screening against zinc containing proteins. We have extended the AutoDock force field to include a specialized potential describing the interactions of zinc-coordinating ligands. This potential describes both the energetic and geometric components of the interaction. The new force field, named AutoDock4_Zn, was calibrated on a data set of 292 crystal complexes containing zinc. Redocking experiments show that the force field provides significant improvement in performance in both free energy of binding estimation as well as in root-mean-square deviation from the crystal structure pose. The new force field has been implemented in AutoDock without modification to the source code

Alkyl vs Aryl Modifications: A Comparative Study on Modular Modifications of Triphenylphosphonium Mitochondrial Vectors

Triphenylphosphonium (TPP+) moieties are commonly conjugated to drug molecules to confer mitochondrial selectivity due to their positive charge and high lipophilicity. Although optimisation of lipophilicity can be achieved by modifying the length of the alkyl linkers between the TPP+ moiety and the drug molecule, it is not always possible. While methylation of the TPP+ moiety is a viable alternative to increase lipophilicity and mitochondrial accumulation, there are no studies comparing these two separate modular approaches. Thus, we have systematically designed, synthesised and tested a range of TPP+ molecules with varying alkyl chain lengths and degree of aryl methylation to compare the two modular methodologies for modulating lipophilicity. The ability of aryl/alkyl modified TPP+ to deliver cargo to the mitochondria was also evaluated by confocal imaging with a TPP+-conjugated fluorescein-based fluorophore. Furthermore, we have employed molecular dynamics simulations to understand the translocation of these molecules through biological membrane model systems. These results provides further insights into the thermodynamics of this process and the effect of alkyl and aryl modular modifications<br /

Prediction of Solvation Free Energies with Thermodynamic Integration Using the General Amber Force Field

Computer-aided drug design (CADD) techniques can be very effective in reducing costs and speeding up drug discovery. The determination of binding and solvation free energies is pivotal for this process and is, therefore, the subject of many studies. In this work, the solvation free energy change (ΔΔ<i>G</i>_solv) for a total of 92 transformations in small molecules was predicted using Thermodynamic Integration (TI). It was our aim to compare experimental and calculated solvation free energies for typical and prime additions considered in drug optimizations, analyzing trends, and optimizing a TI protocol. The results showed a good agreement between experimental and predicted values, with an overestimation of the predicted values for CH₃, halogens, and NH₂, as well as an underestimation for CONH₂, but all fall within ±1 kcal/mol. NO₂ addition showed a larger and systematic underestimation of the predicted ΔΔ<i>G</i>_solv, indicating the need for special attention in these cases. For small molecules, if no experimental data is available, using TI as a theoretical strategy thus appears to be a suitable choice in CADD. It provides a good compromise between time and accuracy

Isomerization of Δ⁵‑Androstene-3,17-dione into Δ⁴‑Androstene-3,17-dione Catalyzed by Human Glutathione Transferase A3-3: A Computational Study Identifies a Dual Role for Glutathione

Glutathione transferases (GSTs) are important enzymes in the metabolism of electrophilic xenobiotic and endobiotic toxic compounds. In addition, human GST A3-3 also catalyzes the double bond isomerization of Δ5-androstene-3,17-dione (Δ⁵-AD) and Δ⁵-pregnene-3,20-dione (Δ⁵-PD), which are the immediate precursors of testosterone and progesterone. In fact, GST A3-3 is the most efficient human enzyme known to exist in the catalysis of these reactions. In this work, we have used density functional theory (DFT) calculations to propose a refined mechanism for the isomerization of Δ⁵-AD catalyzed by GST A3-3. In this mechanism the glutathione (GSH) thiol and Tyr9 catalyze the proton transfer from the Δ⁵-AD C4 atom to the Δ⁵-AD C6 atom, with a rate limiting activation energy of 15.8 kcal·mol^–1. GSH has a dual function, because it is also responsible for stabilizing the negative charge that is formed in the O3 atom of the enolate intermediate. The catalytic role of Tyr9 depends on significant conformational rearrangements of its side chain. Neither of these contributions to catalysis has been observed before. Residues Phe10, Leu111, Ala 208, and Ala 216 complete the list of the important catalytic residues. The mechanism detailed here is based on the GST A3-3:GSH:Δ⁴-AD crystal structure and is consistent with all available experimental data

Mechanism of Glutathione Transferase P1-1-Catalyzed Activation of the Prodrug Canfosfamide (TLK286, TELCYTA)

Canfosfamide (TLK286, TELCYTA) is a prodrug that upon activation by glutathione transferase P1-1 (GST P1-1) yields an anticancer alkylating agent and a glutathione derivative. The rationale underlying the use of TLK286 in chemotherapy is that tumor cells overexpressing GST P1-1 will be locally exposed to the released alkylating agent with limited collateral toxicity to the surrounding normal tissues. TLK286 has demonstrated clinical effects in phase II and III clinical trials for the treatment of malignancies, such as ovarian cancer, nonsmall cell lung cancer, and breast cancer, as a single agent and in combination with other chemotherapeutic agents. In spite of these promising results, the detailed mechanism of GST P1-1 activation of the prodrug has not been elucidated. Here, we propose a mechanism for the TLK286 activation by GST P1-1 on the basis of density functional theory (DFT) and on potential of mean force (PMF) calculations. A catalytic water molecule is instrumental to the activation by forming a network of intermolecular interactions between the active-site Tyr7 hydroxyl and the sulfone and COO^– groups of TLK286. The results obtained are consistent with the available experimental kinetic data and provide an atomistic understanding of the TLK286 activation mechanism