Ion transport through membranes: A computer experiment

Abstract

Gramicidin-A is a linear pentadecapeptide antibiotic, which forms transmembrane channels; these have a number of interesting conductance characteristics [1, 2 and Refs. therein], as for example high specific ion fluxes (a single channel carries about 10 7 sodium ions/sec at 25 °C, 1 M NaCl and 100 mV transmembrane d.d.p.) have a remarkable ion selectivity among the monovalent cations. The permeability ratios with respect to sodium were found to be in following order H +(150) > NH 4 + (8.9) > Cs +(5.8) > Rb +(5.5) > K +(3.9) > Na + (1.0) > Li + (0.33). The channel is impermeable to anions and to divalent cations and it exhibits saturation and maxima in conductance as a function of ion concentration, voltage dependence of single channel currents, ion competition and block, and concentration dependence of permeability ratios. These conductance properties make the Gramicidin-A channel in some respects similar to the Na + and K + transmembrane channels responsible for the excitability of nerve and muscle cells; this enhances the interest in the Gramicidin channel. The Gramicidin-A channel seems to have two binding sites for monovalent cations, as suggested by NMR experiments using 13C marked Gramicidin molecules [2]. The free energy profile for the transport of Na + has also been determined [3]. A number of possible structural models for the Gramicidin channel have been considered [4] involving single helices [5, 6], or double helices [4, 7]. in Urry's model, which seems in agreement with a number of experimental works, two left-handed β 6,3 3,6 Gramicidin helices are held together at their N-termini (heads) by hydrogen bonding to form a channel with a length of 26 Å and a pore diameter of 4 Å. A qualitative mechanism of ion transport and ion selectivity has been proposed [8], arising from the liberation of the carbonyl oxygen into the channel, lining with it negative charges. The general picture of the phenomenon, however, is far from complete. Indeed, other molecular conformations could contribute to the conduction process [4] and even small variations in the conformation of the Gramicidin channel could affect the energetics of channel-ion interactions [1]. In order to help our understanding at the molecular level of some of the above problems concerning the interaction between the Gramicidin-A channel and ions and the role played by water in the ion transport process, we have undertaken computer simulation experiments on this system, assuming Urry's model for the channel. As for similarly large systems previously investigated [9, 10], our initial effort has been directed to the evaluation of pair potentials for the interactions between atoms of the residues and of the backbone, and sodium ion/water molecule. This step, which makes possible Monte Carlo and molecular dynamics simulations, required about one thousand three hundred ab initio computations even considering the Na + ion only. In addition, more than four hundred ab initio computations have been carried out to evaluate pair potentials relative to the interaction between Na +/water molecule and the phospholipid lysophosphatidylethanolamine, which is used to simulate the membrane moiety of the system. Results of Monte Carlo simulations based on the above models and pair potentials are presented [11].