Prediction and Simulation of Motion in
Pairs of Transmembrane a-Helices
Angela Enosh, Sarel J. Fleishman, Nir Ben-Tal and Dan Halperin - Paper .
Abstract
Motivation: Motion in transmembrane (TM) proteins plays an essential role in a variety of biological phenomena.
Thus, developing an automated method for predicting and simulating motion in this class of proteins should result in an
increased level of understanding of crucial physiological mechanisms.
We have developed an algorithm for predicting and simulating motion in TM proteins of the a-helix bundle type.
Our method employs probabilistic motion-planning techniques to suggest possible collision-free motion paths.
The resulting paths are ranked according to the quality of the van-der-Waals interactions between the TM helices.
Our algorithm considers a wide range of degrees of freedom (dofs) involved in the motion, including external and
internal moves. However, in order to handle the vast dimensionality of the problem, we employ some relaxations on
these dofs in a way that is unlikely to rule out the native motion of the protein.
Our algorithm simulates the motion, including all the dofs, and automatically produces a movie that demonstrates it.
Results: Overexpression of the RTK ErbB2 was implicated in causing a variety of human cancers.
Recently, a molecular mechanism for rotation-coupled activation of the receptor was suggested.
We applied our algorithm to investigate the TM domain of this protein, and compared our results to this mechanism.
A motion pathway that was similar to the proposed mechanism ranked first, and motions with partial overlap to this
pathway followed in rank order. In addition, we conducted a negative-control numerical-experiment using Glycophorin A.
Our results confirmed the immobility of this TM protein, resulting in degenerate paths comprising native-like conformations.
Supplementary Material
Movie 1: Motion pathway from Gly668-xxx-Gly672 motif towards Ser656-xxx-Gly660 motif.
Movie 2: Motion pathway from Ser656-xxx-Gly660 motif towards Gly668-xxx-Gly672 motif.
Movie 3: A negative control experiment - Glycophorin A.
Figure 6: Symmetry along the pathway.
Each conformation was evaluated by the symmetry between the two helices. To
this end, one helix was superimposed
on the other using a rotation of 180 degrees around the bisector of the helices’ principal axes. The mean rmsd
between the helices after superposition was 0.57 Angstrom and the standard deviation was 0.17 Angstrom.