Structure of Gramicidin A in a Lipid Bilayer Environment Determined Using Molecular Dynamics Simulations and Solid-State NMR Data

Two different high-resolution structures recently have been proposed for the membrane-spanning gramicidin A channel:  one based on solid-state NMR experiments in oriented phospholipid bilayers (Ketchem, R. R.; Roux, B.; Cross, T. A. Structure 1997, 5, 1655−1669; Protein Data Bank, PDB:1MAG); and one based on two-dimensional NMR in detergent micelles (Townsley, L. E.; Tucker, W. A.; Sham, S.; Hinton, J. F. Biochemistry 2001, 40, 11676−11686; PDB:1JNO). Despite overall agreement, the two structures differ in peptide backbone pitch and the orientation of several side chains; in particular that of the Trp at position 9. Given the importance of the peptide backbone and Trp side chains for ion permeation, we undertook an investigation of the two structures using molecular dynamics simulation with an explicit lipid bilayer membrane, similar to the system used for the solid-state NMR experiments. Based on 0.1 μs of simulation, both backbone structures converge to a structure with 6.25 residues per turn, in agreem...