Human Endothelin converting enzyme (hECE-1) has been widely known for its involvement in hydrolyzing
Aβ peptides at multiple sites. In the present study we have performed molecular dynamics (MD) simulation of crystal
structure complex of hECE-1 and its inhibitor phosphoramidon with Zn ion to understand the dynamic behavior of active
site residues. Root Mean Square Deviation (RMSD) results revealed that enzyme hECE-1 structure was highly stable
throughout the simulation period. The L-leucyl-L-tryptophan moiety and N-phosphoryl moiety of phosphoramidon was
found in the S1 and S2 pockets of hECE-1 respectively. The inhibitor was stabilized by hydrogen bonding interactions
with residues Arg 145, Asn 566, Pro 731 and His 732 of hECE-1. Based on this information molecular docking of hECE-
1 crystal structure with three different structures of Aβ peptides has been performed. Zinc ion interacts with His
607(NE2), His 611(NE2), Glu 667 (OE1, OE2) and backbone oxygen atom of Phe 19 showing catalytic coordination between
Aβ peptide and hECE-1. The unusual orientation of Aβ peptide residues affects hydrophobic interactions and hydrogen
bonding network between hECE-1 and Aβ peptide. The molecular basis of amyloid beta peptide cleavage by
hECE-1 could aid in designing enzyme based therapies to control Aβ peptide concentration in Alzheimer’s patient.
Keywords: Aβ (Amyloid beta), Alzheimer’s disease, hECE (Human Endothelin Converting Enzyme), Phosphoramidon, Molecular
Docking, Molecular dynamics.
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