Molecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol

• Published in: Revista Facultad de Ingeniería no. 98; pp. NP - 128
• Main Authors: Cruz-Jiménez, Juan Carlos, Mercado-Montoya, Marcela, Ostos-Ortíz, Carlos Eduardo, Hernández Validivieso, Alher Mauricio
• Format: Journal Article
• Language: English; Portuguese
• Published: Medellín Universidad de Antioquía 01.03.2021; Facultad de Ingeniería, Universidad de Antioquia; Universidad de Antioquia
• Subjects: Alzheimer's disease; Biology; Cholesterol; complex modes; Computer simulation; Cytotoxicity; Dementia; Dimers; Domains; ENGINEERING, MULTIDISCIPLINARY; Enzymes; Etiology; Health risk assessment; Ligands; Membranes; modal analysis; Molecular dynamics; molecular interaction; Molecular interactions; Peptides; Proteins; Simulation; Structural analysis; interacción molecular; structural analysis; Modal analysis; complex modes; Análisis modal; análisis estructural; modos complejos; molecular interaction
• ISSN: 0120-6230; 2422-2844; 2422-2844
• DOI: 10.17533/udea.redin.20200368

Molecular dynamic (MD) simulation is an approach frequently employed in computational biology for exhaustive sampling of the protein-ligand conformational space. Hence, it is useful for structural analysis and the study of molecular interactions. In this study, we report on a MD simulation protocol to understand the dynamics of β-secretase 1 (BACE1) and 2 (BACE2), widely known to play a critical role in the etiology of Alzheimer’s disease, by a structure change evaluation of their transmembrane domains while inserted in a simulated neural membrane system. We considered two different levels in membrane cholesterol content. Because there is no evidence supporting the capacity of BACE1 and BACE2 to exist as a dimer, single and double (BACE1/BACE1, BACE2/BACE2, BACE1/BACE2) systems, either in parallel or antiparallel orientation, were prepared for each run. Analysis of tridimensional structure of BACE1 and BACE2, after 10ns of MD simulation, revealed a correlation between higher cholesterol levels and both peptide refolding and changes in the secondary structure of both transmembrane domains in single and double systems. Interestingly, our results also indicate a potential interaction in the double system BACE2/BACE2, particularly when the domains had an antiparallel orientation.