Assigning Transmembrane Segments to Helices in Intermediate-Resolution Structures
Angela Enosh (a,*), Sarel J. Fleishman (b), Nir Ben-Tal (b) and Dan Halperin (a)
(a) School of Computer Science, (b) Department of Biochemistry, Tel Aviv University, Ramat Aviv, 69978, Israel, (*) To whom correspondence should be addressed.
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 (<4Ň)
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 proteinís sequence to the helices seen in cryo-EM
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.
Availability: The program and the non-redundant set of protein
structures used here are available at: http://www.cs.tau.ac.il/~angela
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