A molecular dynamics study of an L-type calcium channel model

• Published in: Protein engineering Vol. 15; no. 2; pp. 109 - 122
• Main Authors: Barreiro, Gabriela, Guimarães, Cristiano Ruch Werneck, de Alencastro, Ricardo Bicca
• Format: Journal Article
• Language: English
• Published: England Oxford Publishing Limited (England) 01.02.2002
• Subjects: Amino Acid Sequence; Calcium - physiology; Calcium Channels, L-Type - chemistry; Calcium Channels, L-Type - physiology; Humans; Ion Channel Gating - physiology; Models, Chemical; Models, Molecular; Molecular Sequence Data; Protein Structure, Secondary; Sequence Homology, Amino Acid
• ISSN: 0269-2139; 1741-0126; 1741-0134
• DOI: 10.1093/protein/15.2.109

In this work, we propose a molecular model of the L-type calcium channel pore from the human cardiac alpha1 subunit. Four glutamic acid residues, the EEEE locus, located at highly conserved P loops (also called SS1-SS2 segments) of the alpha1 subunit, molecularly express the calcium channel selectivity. The proposed alpha-helix structure for the SS1 segment, analyzed through molecular dynamics simulations in aqueous-phase, was validated by the plotting of Ramachandran diagrams for the averaged structures and by the analysis of i and i + 4 helical hydrogen bonding between the amino acid residues. The results of the simulation of the calcium channel model with one and two Ca2+ ions at the binding site are in accordance with mutation studies which suggest that the EEEE locus in the L-type calcium channel must form a single high-affinity binding site. These results suggest that the Ca2+ permeation through the channel would be derived from competition between two ions for the only high-affinity binding site. Furthermore, the experimentally observed blocking of the Na+ flux at micromolar Ca2+ concentrations, probably due to the occupancy of the single high-affinity binding site for one Ca2+, was also reproduced by our model.