Noncontact dipole effects on channel permeation. V. Computed potentials for fluorinated gramicidin

Experimental and theoretical calculations indicate that the dipole moment o f the four Trp side chains in gramicidin A (gA) channels modify channel con ductance through long-range electrostatic interactions. Electrostatic ion/s ide-chain interaction energies along the channel were computed with CHARMM using ab initio atom charges for native and 4-, 5-, or 6-fluorinated Trp si de chains. The bulk water reaction to the polar side chains was included us ing the method of images as implemented by Dorigo et al. (1999), and channe l waters in idealized structures were included. Ion/Trp interaction energie s were similar to -0.6 kcal/mol throughout the channel for all four of the native Trp pairs. Channel waters produced a modest reduction in the magnitu de of interactions, essentially offsetting images representing the bulk wat er outside the channel. The effects of side-chain fluorination depended on ring position and, to a lesser extent, residue number. Compared with native Trp, 5-fluorination reduces the translocation barrier with minor effects o n the exit barrier. In contrast, 6-fluorination primarily reduces exit barr ier. 4-Fluorination produces a more complex double-well energy profile. Eff ects of measured side-chain movements resulting from fluorination or change in lipid bilayer were negligible whereas thermal side chain librations cau se large effects, especially in the region of the ion-binding sites.