Exploring the conformational space of membrane protein folds matching distance constraints

The references provided below present a computational technique for generating helix-membrane protein folds matching a predefined set of distance constraints, such as thoseexternal image 1f88_constrainsts.gif obtained from NMR NOE, chemical cross-linking, dipolar EPR and FRET experiments. The purpose of the technique is to provide initial structures for local conformational searches based on either energetic considerations or ad-hoc scoring criteria. In order to properly screen the conformational space, the technique generates an exhaustive list of conformations within a specified root-mean-square deviation (RMSD) where the helices are positioned in order the match the provided distances. Our results indicate that the number of structures decreases exponentially as the number of distances increases, and increases exponentially as the errors associated with the distances increases. We also find the number of solutions to be smaller when all the distances share one helix in common compared to the case where the distances connect helices in a daisy chain manner. We find that for 7 helices, at least 15 distances with errors up to 8 Å are needed to produce a number of solutions that is not too large to be processed by local search refinement procedures. Finally, without energetic considerations, our enumeration technique retrieved the transmembrane domains of Bacteriorhodopsin (PDB entry1c3w), Halorhodopsin (1e12), Rhodopsin (1f88), Aquaporin-1 (1fqy), Glycerol uptake facilitator protein (1fx8), Sensory Rhodopsin (1jgj), and a subunit of Fumarate reductase flavoprotein (1qlaC) with C-alpha level RMSDs of 3.0 Å, 2.3 Å, 3.2 Å, 4.6 Å, 6.0 Å, 3.7 Å and 4.4 Å, respectively.





References:
  1. Brown W.M., Faulon J.L., Sale K. A deterministic algorithm for constrained enumeration of transmembrane protein folds. Comput Biol Chem., 29, 143-150, 2005. [PMID: 15833442]. (link to journal)
  2. Sale K, Faulon J.L., Gray G.A., Schoeniger J.S., Young M.M. Optimal bundling of transmembrane helices using sparse distance constraints. Protein Science, 13, 2613-2627, 2004. [PMID: 15340162]. (.pdf manuscript).
  3. Faulon J.L., Sale K, Young M.M., Exploring the conformational space of membrane protein folds matching distance constraints, Protein Science, 12, 1750-1761, 2003. [PMID: 12876324]. (.pdf)
  4. Faulon, J. L., Rintoul M. D., Young, M. M. Constrained Self-Avoiding Walks: Implications for Protein Structure Determination, J. Phys. A: Gen. Math., 34, 1-20, 2002. (link to journal)