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J Mol Biol. 2017 Feb 3;429(3):390-398. doi: 10.1016/j.jmb.2016.09.005. Epub 2016 Sep 10.

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

Author information

1
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA. Electronic address: almz@umich.edu.
2
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA.

Abstract

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 3.3Å. 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).

KEYWORDS:

NMR structures; energy potentials; single-spanning membrane proteins; web server

PMID:
27622289
DOI:
10.1016/j.jmb.2016.09.005
[Indexed for MEDLINE]

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