Geometry and Topology of Folding Landscapes - Biological Networks - page 146

monomers (Fig. 7.3a). The second (type II) is global torsion of the helical bundle
similar to a cork-screw mechanism, with the net result of inducing an
enlargement of the pore region (Figs. 7.3b and 7.3c). The change in the relative
spacing of the TM2 helices (Shrivastava & Bahar, 2006) was observed to be in
accord with the models based on site-directed spin labeling and EPR
spectroscopy data (Perozo et al. , 1999) and experimental structures of the open
form.
This study reinforces the observation that proteins have an inherent ability to
undergo conformational changes required for their biological function (Ma, 2005;
Bahar et al. , 2007; Tama & Sanejouand, 2001; Xu et al. , 2003). Computational
studies performed by Sansom and coworkers for investigating the dynamics
of inward rectifying potassium channels (Kirs) (Haider et al. , 2005) further
indicated a good agreement (correlation coefficient of 0.87) between the mean-
square fluctuations of Kir3.1 residues obtained from molecular dynamics (MD)
simulations and those predicted by ANM. The lowest frequency mode from
ANM indicated an asymmetric dimer-of-dimers motion, which is also in
agreement with that inferred from MD simulations, suggesting that this
mechanism of motion is a robust property of the structure. (Sansom et al. , 2005).
A good correlation was also reported more recently between ENM results
and site-directed mutagenesis experiments for KcsA and Mthk (Haliloglu & Ben-
Tal, 2008).
nAcetyl Choline Receptor ( nAChR ): Gating via global twist of the quaternary
structur e . As a member of the receptor family of membrane proteins, this
homo- or hetero-pentamer switches between ion-permeable and -impermeable
conformations upon binding or releasing its neurotransmitter substrate,
acetylcholine (ACh). The ACh binding site is located at the boundary between
the subunits in the EC region. Binding of ACh promotes a transient opening of
the channel. Several models have been proposed for the structural transition
mediating the signal transmission (Changeux & Edelstein, 1998; Taly et al. ,
2005; Liu et al. , 2008; Szarecka et al. , 2007). Normal mode analysis on the
complete structure revealed a concerted symmetric quaternary twist motion (Taly
et al. , 2005), with the EC and IC domains rotating in opposite directions resulting
in a wide opening of the pore, compatible with experimental observations.
GNM/ANM analyses (Szarecka et al. , 2007) of structural models based on cryo-
electron microscopy data (Unwin, 2005) also revealed two types of quasi-
symmetric twisting motions: Type I inducing a twisting of ligand binding domain
(LBD) in opposite direction to that of TM and IC domains; and Type II where the