Determination of the protonation state for the catalytic dyad in β-secretase when bound to hydroxyethylamine transition state analogue inhibitors: A molecular dynamics simulation study.
BACE1 is an aspartyl protease of pharmacological interest for its direct participation in Alzheimer's disease (AD) through β-amyloid peptide production. Two aspartic acid residues are present in the BACE1 catalytic region which can adopt multiple protonation states depending on the chemical nature of its inhibitors, i.e., monoprotonated, diprotonated and di-deprotonated states. In the present study a series of protein-ligand molecular dynamics (MD) simulations was carried out to identify the most feasible protonation state adopted by the catalytic dyad in the presence of hydroxyethylamine transition state analogue inhibitors. The MD trajectories revealed that the di-deprotonated state is most prefered in the presence of hydroxyethilamine (HEA) family inhibitors. This appears as a result after evaluating, for all 9 protonation state configurations during the simulation time, the deviations of a set of distances and dihedral angles measured on the ligand, protein and protein-ligand complex with reference to an X-ray experimental BACE1/HEA crystallographic structure. These results will help to clarify the phenomena related to the HEAs inhibitory pathway, and improve HEAs databases' virtual screening and ligand design processes targeting β-secretase protein.
Grupo de Química Bioorgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Colombia.
Carlos
C
Gueto-Tettay
Grupo de Química Bioorgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Colombia.
Roberto
R
Pestana-Nobles
Grupo de Química Bioorgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Colombia. Electronic address: jdrososr@unicartagena.edu.co.
Juan Carlos
JC
Drosos-Ramirez
D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry; D001224:Aspartic Acid / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D005021:Ethylamines / Q000737:chemistry*; D006860:Hydrogen Bonding; D006865:Hydrogenation; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011522:Protons
D016229:Amyloid beta-Peptides; D005021:Ethylamines; D008024:Ligands; D011522:Protons; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
Alzheimer’s disease (AD); Aspartatic dyad; BACE1; Gromacs; Hydroxyethylamine (HEA); Protonation state