TMDOCK: An Energy-Based Method for Modeling α-Helical Dimers in Membranes

- Structures of functional dimers of the single-pass membrane proteins are generally unknown.
- TMDOCK method for the modeling of parallel α-helical homodimers was developed.
- 3D models of dimers are ranked based on the free energy of helix association.
- Of the α-helical dimers, 26 experimental 3D structures were reproduced.
- The method allows the assessment of structural heterogeneity of dimers.

TMDOCK is a novel computational method for the modeling of parallel homodimers formed by transmembrane (TM) α-helices. Three-dimensional (3D) models of dimers are generated by threading a target amino acid sequence through several structural templates, followed by local energy minimization. This is the first method that identifies helix dimerization modes and ranks them based on the calculated free energy of α-helix association. Free energy components include van der Waals, hydrogen bonding, and dipole interactions; side-chain conformational entropy; and solvation energy in the anisotropic lipid environment. TMDOCK reproduced 26 experimental dimeric structures formed by TM α-helices of 21 single-pass membrane proteins (including 4 mutants) with Cα atom rmsd from 1.0 to 3.3 Å. Assessment of dimerization heterogeneity of these TM domains demonstrated that 7 of them have a unique dimer structure, 12 have at least 2 alternative conformations, and 2 have a large number of different association modes. All unique experimental structures of proteins from the first group and eight structures from the second group were reproduced in computations as top-ranked models. A fast version of the method is available through the web server (http://membranome.org/tm_server.php).

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