Exploring mode of phosphoramidon and Aß peptide binding to hECE-1 by molecular dynamics and docking studies.

Human Endothelin converting enzyme (hECE-1) has been widely known for its involvement in hydrolyzing Aß 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 Aß 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 Aß peptide and hECE-1. The unusual orientation of Aß peptide residues affects hydrophobic interactions and hydrogen bonding network between hECE-1 and Aß peptide. The molecular basis of amyloid beta peptide cleavage by hECE-1 could aid in designing enzyme based therapies to control Aß peptide concentration in Alzheimer's patient.

Molecular dynamics simulation and molecular docking studies of Angiotensin converting enzyme with inhibitor lisinopril and amyloid Beta Peptide.

Angiotensin converting enzyme (ACE) cleaves amyloid beta peptide. So far this cleavage mechanism has not been studied in detail at atomic level. Keeping this view in mind, we performed molecular dynamics simulation of crystal structure complex of testis truncated version of ACE (tACE) and its inhibitor lisinopril along with Zn(2+) to understand the dynamic behavior of active site residues of tACE. Root mean square deviation results revealed the stability of tACE throughout simulation. The residues Ala 354, Glu 376, Asp 377, Glu 384, His 513, Tyr 520 and Tyr 523 of tACE stabilized lisinopril by hydrogen bonding interactions. Using this information in subsequent part of study, molecular docking of tACE crystal structure with Aß-peptide has been made to investigate the interactions of Aß-peptide with enzyme tACE. The residues Asp 7 and Ser 8 of Aß-peptide were found in close contact with Glu 384 of tACE along with Zn(2+). This study has demonstrated that the residue Glu 384 of tACE might play key role in the degradation of Aß-peptide by cleaving peptide bond between Asp 7 and Ser 8 residues. Molecular basis generated by this attempt could provide valuable information towards designing of new therapies to control Aß concentration in Alzheimer's patient.