Structural activation pathways from dynamic olfactory receptor-odorant interactions

被引:40
作者
Lai, PC
Singer, MS
Crasto, CJ [1 ]
机构
[1] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06520 USA
[2] Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT 06269 USA
[3] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA
[4] Yale Univ, Sch Med, Yale Ctr Med Informat, New Haven, CT USA
关键词
ligand binding; molecular dynamics; olfactory receptors;
D O I
10.1093/chemse/bji070
中图分类号
B84 [心理学]; C [社会科学总论]; Q98 [人类学];
学科分类号
03 ; 0303 ; 030303 ; 04 ; 0402 ;
摘要
We have simulated an odor ligand's dynamic behavior in the binding region of an olfactory receptor (OR). Our short timescale computational studies (up to 200 ps) have helped identify unprecedented postdocking ligand behavior of ligands. From in vacuo molecular dynamics simulations of interactions between models of rat OR I7 and 10 aldehyde ligands, we have identified a dissociative pathway along which the ligand exits and enters the OR-binding pocket-a transit event. The ligand's transit through the receptor's binding region may mark the beginning of a signal transduction cascade leading to odor recognition. We have graphically traced the rotameric changes in key OR amino acid side chains during the transit. Our results have helped substantiate or refute previously held notions of amino acid contribution to ligand stability in the binding pocket. Our observations of ligand activity when compared to those of experimental (electroolfactogram response) OR-activation studies provide a view to predicting the stability of ligands in the binding pocket as a precursor to OR activation by the ligand.
引用
收藏
页码:781 / 792
页数:12
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