Structure determination of symmetric homo-oligomers by a complete search of symmetry configuration space, using NMR restraints and van der Waals packing
Article first published online: 8 AUG 2006
Copyright © 2006 Wiley-Liss, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 65, Issue 1, pages 203–219, 1 October 2006
How to Cite
Potluri, S., Yan, A. K., Chou, J. J., Donald, B. R. and Bailey-Kellogg, C. (2006), Structure determination of symmetric homo-oligomers by a complete search of symmetry configuration space, using NMR restraints and van der Waals packing. Proteins, 65: 203–219. doi: 10.1002/prot.21091
- Issue published online: 22 AUG 2006
- Article first published online: 8 AUG 2006
- Manuscript Accepted: 15 MAY 2006
- Manuscript Revised: 2 MAY 2006
- Manuscript Received: 22 DEC 2005
- National Institutes of Health. Grant Number: R01 GM 65982
- National Science Foundation. Grant Numbers: EIA-9802068, EIA-0305444
- National Science Foundation. Grant Numbers: IIS-0444544, IIS-0502801
- Smith Family award
- Nuclear magnetic resonance (NMR);
- Structure determination;
- Symmetric homooligomer;
- Membrane protein;
- Configuration space
Structural studies of symmetric homo-oligomers provide mechanistic insights into their roles in essential biological processes, including cell signaling and cellular regulation. This paper presents a novel algorithm for homo-oligomeric structure determination, given the subunit structure, that is both complete, in that it evaluates all possible conformations, and data-driven, in that it evaluates conformations separately for consistency with experimental data and for quality of packing. Completeness ensures that the algorithm does not miss the native conformation, and being data-driven enables it to assess the structural precision possible from data alone. Our algorithm performs a branch-and-bound search in the symmetry configuration space, the space of symmetry axis parameters (positions and orientations) defining all possible Cn homo-oligomeric complexes for a given subunit structure. It eliminates those symmetry axes inconsistent with intersubunit nuclear Overhauser effect (NOE) distance restraints and then identifies conformations representing any consistent, well-packed structure to within a user-defined similarity level.
For the human phospholamban pentamer in dodecylphosphocholine micelles, using the structure of one subunit determined from a subset of the experimental NMR data, our algorithm identifies a diverse set of complex structures consistent with the nine intersubunit NOE restraints. The distribution of determined structures provides an objective characterization of structural uncertainty: backbone RMSD to the previously determined structure ranges from 1.07 to 8.85 Å, and variance in backbone atomic coordinates is an average of 12.32 Å2. Incorporating vdW packing reduces structural diversity to a maximum backbone RMSD of 6.24 Å and an average backbone variance of 6.80 Å2. By comparing data consistency and packing quality under different assumptions of oligomeric number, our algorithm identifies the pentamer as the most likely oligomeric state of phospholamban, demonstrating that it is possible to determine the oligomeric number directly from NMR data. Additional tests on a number of homo-oligomers, from dimer to heptamer, similarly demonstrate the power of our method to provide unbiased determination and evaluation of homo-oligomeric complex structures. Proteins 2006. © 2006 Wiley-Liss, Inc.