title: Ca2+ selectivity of the sarcoplasmic reticulum Ca2+-ATPase at the enzyme-water interface and in the Ca2+ entrance channel.
abstract: The sarcoplasmic reticulum (SR) Ca(2+)-ATPase, a P-type transmembrane protein, can transport Ca(2+) from the cytoplasmic to the luminal side over other cations specifically. The proposed Ca(2+) entrance channel, composed of the main-chain carbonyl oxygen and side-chain carboxyl oxygen atoms of the amino acids, opens on the enzyme surface, just above the biphospholipid layer membrane-water interface, where Trp residues are frequently found. In this work, the physicochemical nature of Ca(2+) selectivity over Mg(2+) on the surface of the SR Ca(2+)-ATPase has been investigated using the density functional theory (DFT) method. The selection process can be regarded as the first step of the specificity of the enzyme to transport Ca(2+). Subsequently, the specificity of the entrance channel to conduct Ca(2+) over other cations has also been explored. As revealed by thermodynamic analyses, either the aromatic or the aliphatic amino acid residues distributed on the surface of Ca(2+)-ATPase have a bigger affinity to Mg(2+) than to Ca(2+), resulting in a concentration decrease of free Mg(2+) in the local region. Thus, Ca(2+) can transport into the Ca(2+)-entrance channel more easily. Whereafter, for a small quantity of Mg(2+) entering this channel accompanying the Ca(2+) current, the strong electrostatic interactions between Mg(2+) and the ligands will limit the activity of this metal ion, which facilitates the weakly bonded Ca(2+) passing through the channel at a relatively high rate, as suggested by the "sticky-pore" hypothesis. Furthermore, the corresponding theoretical investigations have demonstrated that the increase of the ligand electronegativity can enhance their discrimination between these two cations effectively.
authors.affiliation: Key Laboratory for Colloid and Interface Chemistry of Ministry of Education, The Modeling & Simulation Chemistry Division, Shandong University, Jinan 250100, P. R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xiang
authors.forename: Robert I
authors.initials: RI
authors.lastname: Cukier
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Bu
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D002413:Cations, Divalent; D007211:Indoles / Q000378:metabolism; D008024:Ligands; D008274:Magnesium / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D011817:Rabbits; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000737:chemistry / Q000378:metabolism*; D013499:Surface Properties; D013816:Thermodynamics; D014364:Tryptophan / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: D015220:Calcium Channels; D002413:Cations, Divalent; D007211:Indoles; D008024:Ligands; D014867:Water; C030374:indole; D014364:Tryptophan; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D008274:Magnesium; D002118:Calcium