COMPUTATIONAL STUDY OF AIF AND QUINONE COMPOUNDS IN MODULATING APOPTOSIS USING THE DOCKING AND PARAMETRIZED QUANTUM METHODS

• Main Author: Listyawati, Muklisatum
• Format: Dissertations
• Language: Indonesia
• Subjects: Kimia
• Online Access: https://digilib.itb.ac.id/gdl/view/75036
• Institution: Institut Teknologi Bandung

AIF-mitochondria is a protein that is crucial for apoptosis and whose dysregulation has been connected to the emergence of cancer. Mitochondria are organelles that in healthy cells function as energy factories that are important for maintaining cell life. Apoptosis-inducing factor (AIF) is a small protein located in the mitochondrial intermembrane space with active sites, namely FAD and NADH. Quinone compounds have shown potential as anti-cancer agents by targeting mitochondrial function. In this study, we use computational methods, including docking and Divide-and-Conquer Density Functional Tight-Binding Molecular Dynamics (DCDFTBMD) methods, a kind of parametrized quantum calculations, to investigate the interactions between mitochondrial AIF and quinone compounds with anticancer potential. In addition, AIF is a lethal protein which was initially known as a caspase-free effector. In cells that are induced to die, AIF which was originally in the mitochondria will translocate to the cytoplasm, then to the cell nucleus to participate in chromatin condensation and DNA degradation. Recently it was proposed that there is an additional role for AIF, namely its activity in the metabolism of quinone compounds in the presence of menadion (2-methyl-1,4-naphthaquinone; vitamin K3), AIF acts as a NADH: quinone reductase, by facilitating the reduction reaction of quinones to semiquinone compounds. or toxic hydroquinone. Menadione reduction is associated with the speed of the redox cycle which is related to the occurrence of oxidative stress in the cell. In addition to reduction of menadion, there are indications that AIF is involved in arylation via the FAD domain with the antioxidant glutathione (GSH) which forms thiodion compounds which are also toxic. The detailed mechanisms for these two ways of AIF's involvement have yet to be revealed. Therefore, understanding the cellular metabolism of quinones is important in the field of oncology because quinone compounds have been successfully explored in relation to their anti- cancer potential. Laboratory studies and preliminary computational docking studies have been carried out to evaluate and analyze the interactions of the menadion functional groups and AIF residues. This study aims to clarify the role of AIF molecularly using computation using the Docking method and (DCDFTBMD). First of all, this method is used to see the interaction of AIF with the ligands that play a role in AIF activity. Next, we will study the mechanism that occurs in more detail regarding the trend of the role of AIF in the FAD and NAD(P)H domains in the regulation of cell death. First, the mitochondrial AIF homology model was constructed based on available structural templates. The structure of selected quinone compounds is optimized using quantum chemical calculations. The docking method was then used to predict the binding mode and binding affinity of quinone compounds with mitochondrial AIF. Next, molecular dynamics simulations using DCDFTBMD were carried out to explore the dynamic properties of the AIF-quinone complexes. Simulations provide insight into complex stability and interaction dynamics. The computational results show that the AIF Interaction is stronger in the FAD domain (-11.4) than in NADH (-8.4). The interacting residues were Val 232, Glue 163, Ala 141, Thr 259, Arg 171, Arg 284, His 453, and Pro 172. The results of the analysis in this study obtained the AIF energy calculation for the FAD domain and the original ligand. of quinone with DCDFTBMD found that the best position was not in the first order but in a different conformation for each interaction of AIF with the ligand, different residues were found with smaller distances from the docking results. This causes the conformation of the DCDFTBMD calculation to be more accurate. The partial charges of the ligand before and after the complex were calculated using the DCDFTBMD technique, and the results show that the charge in the bond changes to become more negative, indicating polarization as well as the presence of electrostatic bonding. And the metadynamics molecular dynamics simulations show that all the ligands are in the correct active sites.