Folding simulations of gramicidin A into the -helix conformations: Simulated annealing molecular dynamics study

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Gramicidin A is a linear hydrophobic 15-residue peptide which consists of alternating D- and L-amino acids and forms a unique tertiary structure, called the ^6.3-helix, to act as a cation-selective ion channel in the natural conditions. In order to investigate the intrinsic ability of the gramicidin A monomer to form secondary structures, we performed the folding simulation of gramicidin A using a simulated annealing molecular dynamics (MD) method in vacuum mimicking the low-dielectric, homogeneous membrane environment. The initial conformation was a fully extended one. From the 200 different MD runs, we obtained a right-handed ^4.4-helix as the lowest-potential-energy structure, and left-handed ^4.4-helix, right-handed and left-handed ^6.3-helix as local-minimum energy states. These results are in accord with those of the experiments of gramicidin A in homogeneous organic solvent. Our simulations showed a slight right-hand sense in the lower-energy conformations and a quite -sheet-forming tendency throughout almost the entire sequence. In order to examine the stability of the obtained right-handed ^6.3-helix and ^4.4-helix structures in more realistic membrane environment, we have also performed all-atom MD simulations in explicit water, ion, and lipid molecules, starting from these -helix structures. The results suggested that ^6.3-helix is more stable than ^4.4-helix in the inhomogeneous, explicit membrane environment, where the pore water and the hydrogen bonds between Trp side-chains and lipid-head groups have a role to further stabilize the ^6.3-helix conformation. ©2009 American Institute of Physics