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Molecular dynamics simulations of Trp side‐chain conformational flexibility in the gramicidin A channel
Author(s) -
Bingham Nathan C.,
Smith Natasha E. C.,
Cross Timothy A.,
Busath David D.
Publication year - 2003
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.10546
Subject(s) - chemistry , side chain , molecular dynamics , gramicidin , crystallography , native state , helix (gastropod) , monomer , intramolecular force , stereochemistry , chemical physics , computational chemistry , ecology , biochemistry , organic chemistry , membrane , biology , polymer , snail
Gramicidin A (gA) is prototypical peptide antibiotic and a model ion channel former. Configured in the solid‐state NMR β 6.5 ‐helix channel conformation, gA was subjected to 1‐ns molecular dynamics (MD) gas phase simulations using the all‐atom charmm22 force field to ascertain the conformational stability of the Trp side chains as governed by backbone and neighboring side‐chain contacts. Three microcanonical trajectories were computed using different initial atomic velocities for each of twenty different initial structures. For each set, one of the four Trp side chains in each monomer was initially positioned in one of the five non‐native conformations (A. E. Dorigo et al., Biophysical Journal, 1999, Vol. 76, 1897–1908), the other Trps being positioned in the native state, o1. In three additional control simulations, all Trps were initiated in the native conformation. After equilibration, constraints were removed and subsequent conformational changes of the initially constrained Trp were measured. The χ 1 was more flexible than χ 2.1 . The energetically optimal orientation, o1 (Dorigo et al., 1999), was the most stable in all four Trp positions (9, 11, 13, 15) and remained unchanged for the entire 1 ns simulation in 19 of 24 trials. Changes in χ 1 from each of the 5 suboptimal states occur readily. Two of the non‐native conformations reverted readily to o1, whereas the other three converted to an intermediate state, i2. There were frequent interconversions between i2 and o1. We speculate that experimentally observed Trp stability is caused by interactions with the lipid–water interface, and that stabilization of one of the suboptimal conformations in gA, such as i2, by lipid headgroups could produce a secondary, metastable conformational state. This could explain recent experimental studies of differences in the channel conductance dispersity between gA and a Trp‐to‐Phe gA analog, gramicidin M (gM, J. C. Markham et al., Biochimica et Biophysica Acta, 2001, Vol. 1513, 185–192). © 2003 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 71: 593–600, 2003