| First Author | Harpole TJ | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 31 | Pages | E3196-205 |
| PubMed ID | 25049389 | Mgi Jnum | J:212233 |
| Mgi Id | MGI:5578377 | Doi | 10.1073/pnas.1408950111 |
| Citation | Harpole TJ, et al. (2014) Side-chain conformation at the selectivity filter shapes the permeation free-energy landscape of an ion channel. Proc Natl Acad Sci U S A 111(31):E3196-205 |
| abstractText | On the basis of single-channel currents recorded from the muscle nicotinic acetylcholine receptor (AChR), we have recently hypothesized that the conformation adopted by the glutamate side chains at the first turn of the pore-lining alpha-helices is a key determinant of the rate of ion permeation. In this paper, we set out to test these ideas within a framework of atomic detail and stereochemical rigor by conducting all-atom molecular dynamics and Brownian dynamics simulations on an extensively validated model of the open-channel muscle AChR. Our simulations provided ample support to the notion that the different rotamers of these glutamates partition into two classes that differ markedly in their ability to catalyze ion conduction, and that the conformations of the four wild-type glutamates are such that two of them "fall" in each rotamer class. Moreover, the simulations allowed us to identify the mm (chi1 congruent with -60 degrees ; chi2 congruent with -60 degrees ) and tp (chi1 congruent with 180 degrees ; chi2 congruent with +60 degrees ) rotamers as the likely conduction-catalyzing conformations of the AChR's selectivity-filter glutamates. More generally, our work shows an example of how experimental benchmarks can guide molecular simulations into providing a type of structural and mechanistic insight that seems otherwise unattainable. |
