Energy profiles in the acetylcholine receptor (AChR) channel The MII‐helix model and the role of the remaining helices

Abstract

It is demonstrated by theoretical computations that no favorable energy profile for cation transfer can be obtained in a model of the AChR channel constructed with the sole five MI1 helices of the inner wall. A favorable profile is obtained upon including the effect of the remaining helices of the five subunits. The decisive role, for the exit of the ion, of the charged residues situated at the N-terminal of the MI1 segments, established before, is underlined further. The role of the other elements of the channel wall (peptide carbonyl oxygens, hydrocarbon residues and polar side chains) is analyzed.Acetylcholine receptor channel; MII-helix model; Helix dipole, a-; Subunit dipole; Na+ energy profile

Structure and function of channels and channelogs as studied by computational chemistry

“…We use Madison's coordinates without further optimization for the presence of water or ions in the channel interior, except that we optimize the orientation of the -OH side chain of the five SER 8 residues in two extreme configurations by allowing the H to rotate maximally toward (for anions) or away (for cations) from the channel axis. The present findings supplement those of an earlier modelling of the AChR channel by Furois-Corbin and Pullman [37][38][39] who considered a number of alternative structures.…”

“…Also notice that the energy level in the channel is elevated over that in solution by only about 13 kcal/ M, much less than would occur on taking a Cs + ion out of water into a low dielectric medium. This supports the conclusion of Furois-Corbin and Pullman [36][37][38] that bundles of apolar alpha helices can provide a permeation pathway for ions (also see [56]). It is, however, apparent that the nonspecific interactions with the polyglycine backbone are insufficient to make this structure almost as favorable for cation permeation as it is when lined with polar residues (compare this with the profile for the wildtype channel).…”

“…Though the helix dipole effect may be less severe in the native channel, where opposing dipoles from other antiparallel alpha helixes are present [38,43], the dipole effects are not likely to be completely neutralized in the channel if M2 lies closest to the channel axis, as is believed [36,37,43]. It should therefore be of considerable interest that differential ionization of the rings of carboxyl and amino residues known to be present at the ends of the channel can produce an almost perfect compensation of such a dipole barrier, as will now be demonstrated.…”

Structure modeling of the acetylcholine receptor channel and related ligand gated channels

“…The binding energy of a single ion in the model described in this article is found to be in the order of 50 kcal tool-1 (Figure 7). Similar binding energies are found in other modeling studies [44,45,[69][70][71]. It is known from electrolyte theory that, at equilibrium, charges tend to become neutralized within a Debye length [72].…”

The Permeation Pathway of Neurotransmitter-Gated Ion Channels

“…Earlier hypotheses (48,59) fe atured the charged amphipathic MA regions, now thought to be intracellular. (e) Some structural models have also served as the basis for simulations of free energy experienced by probe ions as they move through the channel (44,52,53).…”