title: A systematic search method for the identification of tightly packed transmembrane parallel alpha-helices.
abstract: Membrane proteins play a major role in number of biological processes such as signaling pathways. The determination of the three-dimensional structure of these proteins is increasingly important for our understanding of their structure-function relationships. Due to the difficulty in isolating membrane proteins for X-ray diffraction studies, computational techniques are being developed to generate the 3D structures of TM domains. Here, we present a systematic search method for the identification of energetically favorable and tightly packed transmembrane parallel alpha-helices. The first step in our systematic search method is the generation of 3D models for pairs of parallel helix bundles with all possible orientations followed by an energy-based filter to eliminate structures with severe non-bonded contacts. Then, a RMS-based filter was used to cluster these structures into families. Furthermore, these dimers were energy minimized using molecular mechanics force field. Finally, we identified the tightly packed parallel alpha-helices by using an interface surface area. To validate our search method, we compared our predicted GlycophorinA dimer structures with the reported NMR structures. With our search method, we are able to reproduce NMR structures of GPA with 0.9A RMSD. In addition, by considering the reported mutational data on GxxxG motif interactions, twenty percent of our predicted dimers are within in the 2.0A RMSD. The dimers obtained from our method were used to generate parallel trimeric and tetramer TM structures of GPA and found that the structure of GPA might exist only in a dimer form as reported earlier.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road NW, Washington DC 20057, USA.
authors.forename: Nagaraju
authors.initials: N
authors.lastname: Akula
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Pattabiraman
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D030562:Databases, Protein; D019281:Dimerization; D006021:Glycophorins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015203:Reproducibility of Results; D012399:Rotation; D020539:Sequence Analysis, Protein
chemical_list: D006021:Glycophorins; D008565:Membrane Proteins; D046912:Multiprotein Complexes