RESUMEN
ND1 subunit possesses the majority of the inhibitor binding domain of the human mitochondrial respiratory complex I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, that some metabolites from Annona muricata called acetogenins have important biological activities, such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine mitochondrial respiratory complex I by bis-tetrahydrofurans acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human mitochondrial respiratory complex I. In this work, we evaluate the in silico molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, quantum mechanical optimizations, molecular dynamics simulations and the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known mitochondrial respiratory complex I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger binding free energy compared to the rotenone complex. Detailed analysis of the binding free energy shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of the mitochondrial respiratory complex I.
RESUMEN
The aggregation of proteins in the brain is one of the main features of neurodegenerative diseases. In Alzheimer's disease, the abnormal aggregation of Aß-42 is due to intrinsic and extrinsic factors. The latter is due to variations in the environment, such as temperature, salt concentration, and pH. We evaluated the effect of protonation/deprotonation of residues that are part of trimeric and pentameric oligomers at pH 5, pH 6, and pH 7. Molecular dynamics simulation at 200 ns in the canonical ensemble was implemented. The results have revealed that histidine, glutamic acid, and aspartic acid residues showed a protonation/deprotonation effect in oligomers. The root mean square deviation analysis was used to analyze the structural stability at different pHs. We found an increase in hydrophobicity in the side chains of the trimer, while in the pentamer, the structural instability of a compact structure at pH 5 caused the hydrophobic core to open, revealing the hydrophobic region to the environment. At this point, we believe that conformational changes mediated by pH are essential in the aggregation of Aß-42 oligomers.
Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Fragmentos de Péptidos/genética , Agregación Patológica de Proteínas/genética , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos/genética , Péptidos beta-Amiloides/química , Ácido Aspártico/química , Ácido Aspártico/genética , Histidina/química , Histidina/genética , Humanos , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Simulación de Dinámica Molecular , Fragmentos de Péptidos/química , Agregación Patológica de Proteínas/patología , Conformación Proteica , Multimerización de Proteína/genéticaRESUMEN
A theoretical approach was used to evaluate the antioxidant capacity of 20 flavonoids reported in Annona muricata leaves. The theoretical study was at the GGA level using the wB97XD functional and the cc-pvtz basis set. The calculations were performed in gas phase and implicit solvent phase. The flavonol robinetin (03c) and the flavanol gallocatechin (01c) are species that exhibited the best antioxidant capacity in the HAT, SEPT, and SPLET mechanisms. On the other hand, in the SET I mechanism, flavonol quercetin (03b) was the best, and in the SET II mechanism, the most favored species is the flavanol catechin (01a). However, these species do not achieve to overcome the antioxidant capacity presented by the Trolox.