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Assigning Transmembrane Segments to Helices in Intermediate-resolution Structures

Helix distribution
The distribution of the starting points of the second helices
in 3D-space derived from helix-loop-helix motifs with loops
of 3 amino-acids. (The order of the two helices was
specified from the N- to the C-terminus.)


Motivation: Transmembrane (TM) proteins that form α-helix bundles constitute approximately 50% of contemporary drug targets. Yet, it is difficult to determine their high-resolution (< 4Å) structures. Some TM proteins yield more easily to structure determination using cryo electron microscopy (cryo-EM), though this technique most often results in lower resolution structures, precluding an unambiguous assignment of TM amino-acid sequences to the helices seen in the structure. We present computational tools for assigning the TM segments in the protein’s sequence to the helices seen in cryo-EM structures.

Results: The method examines all feasible TM helix assignments and ranks each one based on a score function that was derived from loops in the structures of soluble α-helix bundles. A set of the most likely assignments is then suggested. We tested the method on eight TM chains of known structures such as bacteriorhodopsin and the lactose permease. Our results indicate that many assignments can be rejected at the outset, since they involve the connection of pairs of remotely placed TM helices. The correct assignment received a high score, and was ranked highly among the remaining assignments. For example, in the lactose permease, which contains 12 TM helices, most of which are connected by short loops, only 12 out of 479 million assignments were found to be feasible, and the native one was ranked first.


  • A. Enosh, S.J. Fleishma, N. Ben-Tal and D. Halperin
    Assigning transmembrane segments to helics in intermediate-resolution structures
    Proc. Twelfth International Conference on Intelligent Systems for Molecular Biology (ISMB), held jointly with the Third European Conference on Computational Biology (ECCB), Glasgow, July-August, 2004, pp. 122-129.
    [pdf] [bibtex]


Angela Enosh hompage contact
Sarel J. Fleishman contact
Nir Ben-Tal
Dan Halperin
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