Simulation of the Positive Inotropic Peptide S100A1ct in Aqueous Environment by Gaussian Accelerated Molecular Dynamics

The S100A1ct peptide, consisting of the C-terminal 20 residues of the S100A1 protein fused to an N-terminal 6-residue hydrophilic tag, has been found to exert a positive inotropic effect, resulting in improved contractile performance of failing cardiac and skeletal muscle without arrhythmic side-effects. The S100A1ct peptide thus has high potential for the treatment of acute heart failure. As a step toward understanding its molecular mechanism of action, and to provide a basis for peptidomimetic design to optimize its properties, we here describe de novo structure predictions and molecular dynamics simulations to characterize the conformational landscape of S100A1ct in aqueous environment. In S100A1, the C-terminal 20 residues form an α-helix, but de novo peptide structure predictions indicate that other conformations are also possible. Conventional molecular dynamics simulations in implicit and explicit solvent corroborated this finding. To ensure adequate sampling, we performed simulations of a tagged 10-residue segment of S100A1ct, and we carried out Gaussian accelerated molecular dynamics simulations of the peptides. These simulations showed that although the helical conformation of S100A1ct was the most energetically stable, the peptide can adopt a range of kinked conformations, suggesting that its activity may be related to its ability to act as a conformational switch.