Open AccessMolecular dynamics simulations of Alzheimer's BACE1 and BACE2 transmembrane domains in neurons: Impact of cholesterol
Author(s) -
Juan C. Cruz,
Marcela Mercado Montoya,
C. Ostos,
Alher Mauricio Hernández-Valdivieso
Publication year - 2020
Publication title -
revista facultad de ingeniería universidad de antioquia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.16
H-Index - 12
eISSN - 2422-2844
pISSN - 0120-6230
DOI - 10.17533/udea.redin.20200368
Subject(s) - antiparallel (mathematics) , transmembrane protein , molecular dynamics , biophysics , transmembrane domain , chemistry , computer science , computational biology , biology , membrane , physics , biochemistry , receptor , computational chemistry , quantum mechanics , magnetic field
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.