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Molecular dynamics simulation exploration of cooperative migration mechanism of calcium ions in sarcoplasmic reticulum Ca 2+ ‐ATPase
Author(s) -
Huang Yongqi,
Li Huifang,
Bu Yuxiang
Publication year - 2009
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.21219
Subject(s) - chemistry , calcium , binding site , ion , molecular dynamics , endoplasmic reticulum , calcium atpase , atpase , cytoplasm , biophysics , active site , calcium binding protein , crystallography , biochemistry , enzyme , computational chemistry , biology , organic chemistry
Abstract Calcium ATPase is a member of the P‐type ATPase, and it pumps calcium ions from the cytoplasm into the reticulum against a concentration gradient. Several X‐ray structures of different conformations have been solved in recent years, providing basis for elucidating the active transport mechanism of Ca 2+ ions. In this work, molecular dynamics (MD) simulations were performed at atomic level to investigate the dynamical process of calcium ions moving from the outer mouth of the protein to their binding sites. Five initial locations of Ca 2+ ions were considered, and the simulations lasted for 2 or 6 ns, respectively. Specific pathways leading to the binding sites and large structural rearrangements around binding sites caused by uptake of calcium ions were identified. A cooperative binding mechanism was observed from our simulation. Firstly, the first Ca 2+ ion binds to site I , and then, the second Ca 2+ ion approaches. The interactions between the second Ca 2+ and the residues around site I disturb the binding state of site I and weaken its binding ability for the first bound Ca 2+ . Because of the electrostatic repulsion of the second Ca 2+ and the electrostatic attraction of site II , the first bound Ca 2+ shifts from site I to site II . Concertedly, the second Ca 2+ binds to site I , forming a binding state with two Ca 2+ ions, one at site I and the other at site II . Both of Glu908 and Asp800 coordinate with the two Ca 2+ ions simultaneously during the concerted binding process, which is believed to be the hinge to achieve the concerted binding. In our simulations, four amino acid residues that serve as the channel to link the outer mouth and the binding sites during the binding process were recognized, namely Tyr837, Tyr763, Asn911, and Ser767. The analyses regarding the activity of the proteins via mutations of some key residues also supported our cooperative mechanism. © 2009 Wiley Periodicals, Inc. J Comput Chem 2009