Exploring ligand dissociation pathways from aminopeptidase N using random acceleration molecular dynamics simulation.
Aminopeptidase N (APN) is a zinc-dependent ectopeptidase involved in cell proliferation, secretion, invasion, and angiogenesis, and is widely recognized as an important cancer target. However, the mechanisms whereby ligands leave the active site of APN remain unknown. Investigating ligand dissociation processes is quite difficult, both in classical simulation methods and in experimental approaches. In this study, random acceleration molecular dynamics (RAMD) simulation was used to investigate the potential dissociation pathways of ligand from APN. The results revealed three pathways (channels A, B and C) for ligand release. Channel A, which matches the hypothetical channel region, was the most preferred region for bestatin to dissociate from the enzyme, and is probably the major channel for the inner bound ligand. In addition, two alternative channels (channels B and C) were shown to be possible pathways for ligand egression. Meanwhile, we identified key residues controlling the dynamic features of APN channels. Identification of the dissociation routes will provide further mechanistic insights into APN, which will benefit the development of more promising APN inhibitors. Graphical Abstract The release pathways of bestatin inside active site of aminopeptidase N were simulated using RAMD simulation.
Department of Medicinal Chemistry, School of Pharmaceutical Science, NanChang University, 461, BaYi Road, NanChang, 330006, People's Republic of China.
Ya
Y
Liu
Department of Medicinal Chemistry, School of Pharmaceutical Science, NanChang University, 461, BaYi Road, NanChang, 330006, People's Republic of China. tugg199@yahoo.com.
GuoGang
G
Tu
Department of Medicinal Chemistry, School of Pharmaceutical Science, NanChang University, 461, BaYi Road, NanChang, 330006, People's Republic of China.
XiaoPing
X
Lai
Department of Medicinal Chemistry, School of Pharmaceutical Science, NanChang University, 461, BaYi Road, NanChang, 330006, People's Republic of China.
BinHai
B
Kuang
Department of Medicinal Chemistry, School of Pharmaceutical Science, NanChang University, 461, BaYi Road, NanChang, 330006, People's Republic of China.
ShaoHua
S
Li
D001665:Binding Sites / Q000502:physiology; D018826:CD13 Antigens / Q000378:metabolism*; D020134:Catalytic Domain / Q000502:physiology; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation
D008024:Ligands; D018826:CD13 Antigens
Aminopeptidase N; Dissociation pathways; Molecular dynamics