Biophys J, September 2001, p. 1255-1264, Vol. 81, No. 3

Noncontact Dipole Effects on Channel Permeation. V. Computed Potentials for Fluorinated Gramicidin

Dean G. Anderson,^* Randall B. Shirts, Timothy A. Cross, and David D. Busath^*

 ^*Zoology Department and Center for Neuroscience and  Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, and  Center for Interdisciplinary Magnetic Resonance at the National High Magnetic Field Laboratory, Institute of Molecular Biophysics and Department of Chemistry, Florida State University, Tallahassee, Florida 32306 USA

Experimental and theoretical calculations indicate that the dipole moment of the four Trp side chains in gramicidin A (gA) channels modify channel conductance through long-range electrostatic interactions. Electrostatic ion/side-chain interaction energies along the channel were computed with CHARMM using ab initio atom charges for native and 4-, 5-, or 6-fluorinated Trp side chains. The bulk water reaction to the polar side chains was included using the method of images as implemented by Dorigo et al. (1999), and channel waters in idealized structures were included. Ion/Trp interaction energies were ~0.6 kcal/mol throughout the channel for all four of the native Trp pairs. Channel waters produced a modest reduction in the magnitude of interactions, essentially offsetting images representing the bulk water 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 on the exit barrier. In contrast, 6-fluorination primarily reduces exit barrier. 4-Fluorination produces a more complex double-well energy profile. Effects of measured side-chain movements resulting from fluorination or change in lipid bilayer were negligible whereas thermal side chain librations cause large effects, especially in the region of the ion-binding sites.

Biophys J, September 2001, p. 1255-1264, Vol. 81, No. 3
© 2001 by the Biophysical Society   0006-3495/01/09/1255/10  $2.00

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