title: Binding conformation prediction between human acetylcholinesterase and cytochrome c using molecular modeling methods.
abstract: The acetylcholinesterase (AChE) is important to terminate acetylcholine-mediated neurotransmission at cholinergic synapses. The pivotal role of AChE in apoptosome formation through the interactions with cytochrome c (Cyt c) was demonstrated in recent study. In order to investigate the proper binding conformation between the human AChE (hAChE) and human Cyt c (hCyt c), macro-molecular docking simulation was performed using DOT 2.0 program. The hCyt c was bound to peripheral anionic site (PAS) on hAChE and binding mode of the docked conformation was very similar to the reported crystal structure of the AChE and fasciculin-II (Fas-II) complex. Two 10ns molecular dynamics (MD) simulations were carried out to refine the binding mode of docked structure and to observe the differences of the binding conformations between the absent (Apo) and presence (Holo) of heme group. The key hydrogen bonding residues between hAChE and hCyt c proteins were found in Apo and Holo systems, as well as each Tyr341 and Trp286 residue of hAChE was participated in cation-pi (π) interactions with Lys79 of hCyt c in Apo and Holo systems, respectively. From the present study, although the final structures of the Apo and Holo systems have similar binding pattern, several differences were investigated in flexibilities, interface interactions, and interface accessible surface areas. Based on these results, we were able to predict the reasonable binding conformation which is indispensable for apoptosome formation.
authors.affiliation: Division of Applied Life Science (BK21 Program), Research Institute of Natural Science (RINS), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Songmi
authors.initials: S
authors.lastname: Kim
authors.forename: Yuno
authors.initials: Y
authors.lastname: Lee
authors.forename: Prettina
authors.initials: P
authors.lastname: Lazar
authors.forename: Minky
authors.initials: M
authors.lastname: Son
authors.forename: Ayoung
authors.initials: A
authors.lastname: Baek
authors.forename: Sundarapandian
authors.initials: S
authors.lastname: Thangapandian
authors.forename: Na Young
authors.initials: NY
authors.lastname: Jeong
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000838:Anions / Q000737:chemistry / Q000378:metabolism; D053478:Apoptosomes / Q000096:biosynthesis; D001665:Binding Sites; D018360:Crystallography, X-Ray; D045304:Cytochromes c / Q000737:chemistry / Q000378:metabolism*; D006418:Heme / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment
chemical_list: D000838:Anions; D053478:Apoptosomes; D006418:Heme; D045304:Cytochromes c; D000110:Acetylcholinesterase