Proteome-Wide Modeling of Transmembrane Alpha-Helical Homodimers by TMDOCK

Abstract

A novel energy-based method, TMDOCK, has been developed for ab initio modeling of 3D structures of parallel homodimers in membranes. Instead of exploring the entire conformational space, the method employs a fast template-driven global energy optimization procedure that combines the knowledge of geometrically feasible packing arrangements and local energy minimization with a novel force field. Ranking and selection of optimal dimerization modes is based on the calculated free energy of α-helix association (ΔGassoc) which includes van der Waals, hydrogen bonding and dipole-dipole interactions between helices, side chain conformational entropy, and solvation energy in the anisotropic lipid environment. The fast version of the TMDOCK method is available through the web server (http://membranome.org/tm_server.php).TMDOCK successfully reproduced 26 experimental dimeric structures formed by transmembrane (TM) α-helices of 21 single-pass membrane proteins (including 4 mutants) with Cα atom r.m.s.d. from 1.0 to 3.3 A. Additional testing demonstrated consistency of calculated dimer structures with published TOXCAT, mutagenesis, or other experimental data for more than 80 bitopic proteins. Subsequent application of the method to 6041 bitopic proteins from six proteomes included in the Membranome database (membranome.org) shows that ∼70% of the proteins tend to form stable dimers with ΔGassoc<-3 kcal/mol. Results of modeling indicate three different types of dimerization behavior of TM α-helices. A unique dimerization mode is usually observed for TM domains carrying a single GxxxG-like motif, interhelical disulfide bridges, or polar residues in the middle of a helix. Proteins with several GxxxG-like motifs usually have a few dimerization modes with similar energies. Proteins with Phe-rich sequences often show multiple helix association modes. The preferred modes of dimerization are frequently evolutionarily conserved (e.g. in cadherin, HLA histocompatibility antigen, receptor tyrosine kinase, and cytochrome P450 families), but they can also change even after a single mutation.