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Abstract

Grove et al. have demonstrated L-type Ca2+ channel activity of a synthetic channel peptide (SCP) composed of four helices (sequence: DPWNVFDFLI10VIGSIIDVIL20SE) tethered by their C-termini to a nanopeptide template. We sought to obtain the optimal conformations of SCP and locate the binding sites for Ca2+ and for the dihydropyridine ligand nifedipine. Eight Ca2+ ions were added to neutralize the 16 acidic residues in the helices. Eight patterns of the salt bridges between Ca2+ ions and pairs of the acidic residues were calculated by the Monte Carlo-with-energy-minimization (MCM) protocol. In the energetically optimal conformation, two Ca2+ ions were bound to Asp-1 residues at the intracellular side of SCP, and six Ca2+ ions were arrayed in two files at the diametrically opposite sides of the pore, implying a Ca2+ relay mechanism. Nine modes of nifedipine binding to SCP were simulated by the MCM calculations. In the energetically optimal mode, the ligand fits snugly in the pore. The complex is stabilized by Ca2+ bound between two Asp-17 residues and hydrophilic groups of the ligand. The latter substitute water molecules adjacent to Ca2+ in the ligand-free pore and thus do not obstruct Ca2+ relay. The ligand-binding site is proximal to a hydrophobic bracelet of Ile-10 residues whose rotation is sterically hindered. In some conformations, the bracelet is narrow enough to block the permeation of the hydrated Ca2+ ions. The bracelet may thus act as a "gate" in SCP. Nifedipine and (R)-Bay K 8644, which act as blockers of the SCP, extend a side-chain hydrophobic moiety toward the Ile-10 residues. This would stabilize the pore-closing conformation of the gate. In contrast, the channel activator (S)-Bay K 8644 exposes a hydrophilic moiety toward the Ile-10 residues, thus destabilizing the pore-closing conformation of the gate.