Linear gramicidins with one, two, or three Trp----Phe substitutions in the gramicidin A sequence form beta 6.3-helical channels that have widely varying conductances and average durations. The variations in single-channel conductance and average duration are uncoupled. The single-channel conductance decreases as a monotonic function of the number of Trp----Phe substitutions, and the relative conductance decrease induced by a given Trp----Phe substitution is only weakly affected by substitutions at other positions. These results suggest that each Trp influences the conductance independently, most likely through electrostatic interactions between the Trp dipole(s) and the permeant ion (as was deduced previously for aromatic side-chain substitutions at position one [Koeppe, R. E., Mazet, J.-L., & Andersen, O. S. (1990) Biochemistry 29 (2), 512-520]). Trp----Phe substitutions exert a complex, nonadditive influence on average duration as well as the energetics of heterodimer formation. These changes are presumably due to sequence-specific differences in the channel's surface chemistry--which may be related to ability of the Trp indole NH moieties to form hydrogen bonds with the lipid backbone oxygens and/or interfacial H2O.

In integral membrane proteins the amphipathic aromatic amino acid residues tryptophan and tyrosine tend to be localized at membrane/solution interface. The interfacial location of these residues is likely to be significant for membrane protein structure and function. Trp and Tyr have complex chemical characteristics, however, and it is difficult to deduce how these side chains determine protein structure and function. Specifically, Trp and Tyr not only are amphipathic but also dipolar, and electrostatic interactions that involve the side chain dipoles could be important for function. We evaluate the importance of the Trp dipole moment for ion channel function by replacing Trp residues in gramicidin A by the more polar 5-F-Trp and monitoring the ensuing changes in the conductance of membrane-spanning gramicidin channels. Trp → 5-F-Trp substitutions increase the conductance of the sequence-substituted channels, and we conclude that Trp side chains increase ion permeability through electrostatic interactions with the permeant cations.

The volume and severity of pulmonary emphysema in individual lungs were measured by means of quantitative computed tomography (CT) studies in 28 patients (14 women, 14 men, median age 65 yr) who underwent either bilateral (n = 15) or unilateral (n = 13) lung volume reduction surgery (LVRS). Spirometric, total body plethysmographic, and CT data (at TLC and RV) were correlated before and after LVRS. Lung volumes determined by CT correlated well with volumes obtained by total body plethysmography (p < 0.0001). For individual lungs after LVRS, CT-derived mean lung capacity decreased 13% and residual volume 20% (p < 0.00001 for each), while mean total functional lung volume (TFLV, defined as the volume of lung with CT attenuation greater than -910 Hounsfield units) increased 9% (p < 0.01), and the mean ratio of the air space to tissue space volume (V(AS)/V(TS)) decreased more at RV (23%) than at TLC (14%) (p < 0.0005 for each). In contrast, unilateral LVRS did not affect exhalation from the unoperated lung (2% reduction in RV, p = NS). The magnitude of the postoperative response (CT-derived TLC, RV, TFLV, V(AS)/V(TS)) of each operated lung was comparable for unilateral and bilateral LVRS. Thus, a lung's response to LVRS was independent from that of the contralateral lung. Moreover, postoperative alterations in TFLV and FEV1 correlated significantly (r = 0.80, p < 0.0001), which suggests that the expansion of functioning tissue may contribute to the mechanism by which LVRS palliates airway obstruction.

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