Building a structural model for transient receptor potential channels: Possibilities and Limitations

B. Minofar¹, V. Zayats¹, N. Kulik¹, A. Samad¹, T. Stockner² and R. Ettrich¹

¹Laboratory of High Performance Computing, Institute of Systems Biology and Ecology, Academy of Sciences of the Czech Republic, and Institute of Physical Biology, University of South Bohemia, Zamek 136, 37333 Nove Hrady, Czech Republic

²Bioresources, Austrian Research Centers GmbH - ARC, 2444 Seibersdorf, Austria

Transient receptor potential (TRP) channels are a large superfamily of nonselective cation channels that play an important role in many sensory functions. In the absence of high resolution TRP channel structural data, structural prediction and computational modeling is the only possibility to help with the interpretation of experimental data on an atomic and structural level. TRP channels are characterized by six transmembrane domains and a short, pore-forming hydrophobic stretch between the fifth and sixth transmembrane domain. Many TRP channels have a long amino terminus containing several ankyrin-repeat domains and a C-terminal domain on the cytoplasmic side of the membrane. We demonstrate on two examples, the transient receptor potential vanilloid receptor-1, which is a cation channel present in sensory nerve endings, and the transient receptor potential TRPA1 as a candidate for a mechanically gated transduction channel, the possibilities and limitations of computational modeling. Starting with secondary structure prediction and prediction of transmembrane regions, over fold prediction, threading and homology modeling up to molecular dynamics in an explicit phoshatidyl oleoyl phosphatidylcholine membrane and ligand docking calculations, a wide variety of attempts are made to gain structural insides. Their reliability and confrontation with experimentally gained data is discussed.

Supported by AVOZ60870520 and by MSMT CR LC06010 and MSM6007665808.