Protein Distance Constraints

Lund, O., Frimand, K., Gorodkin, J., Bohr, H Bohr, J., Hansen, J. Brunak, S. (1997). Protein distance constraints predicted by neural networks and probability density functions. Protein Eng 10,1241-8. 

The amount of computation necessary to try many conformers can be greatly reduced if a portion of the structure is known. One way to determine a portion of the structure experimentally is to obtain some of the internuclear distances from two-dimensional NMR experiments, as predicted by the nuclear Over-hauser effect (NOE). Once a set of distances are determined, they can be used as constraints within a conformation search. This has been particularly effective for predicting protein structure since it is very difficult to obtain crystallographic structures of proteins. It is also possible to define distance constraints based on the average bond lengths and angles, if we assume these are fairly rigid while all conformations are accessible. 

TF Flavel. An evaluation of computational strategies for use m the determination of protein structure from distance constraints obtained by nuclear magnetic resonance. Prog Biophys Mol Biol 56 43, 1991. 

W Braun, N. Go. Calculation of protein conformations by proton—proton distance constraints A new efficient algorithm. J Mol Biol 186 611-626, 1985. 

Distance constraints are used to derive possible structures of a protein molecule... 

In NMR the magnetic-spin properties of atomic nuclei within a molecule are used to obtain a list of distance constraints between those atoms in the molecule, from which a three-dimensional structure of the protein molecule can be obtained. The method does not require protein crystals and can be used on protein molecules in concentrated solutions. It is, however, restricted in its use to small protein molecules. 

In de novo three-dimensional structure determinations of proteins in solution by NMR spectroscopy, the key conformational data are upper distance limits derived from nuclear Overhauser effects (NOEs) [11, 14]. In order to extract distance constraints from a NOESY spectrum, its cross peaks have to be assigned, i.e. the pairs of hydrogen atoms that give rise to cross peaks have to be identified. The basis for the NOESY assignment... 

Particularly important information will come from additional distance constraints between the receptor and G protein, such as novel cross-links or interprobe measurements from fluorescence or electron paramagnetic resonance spectroscopy. Initially, relatively few long-range distance constraints would be necessary to define the relative orientation of the receptor and G protein, which is a fundamental but unanswered question about the complex. Once the proper orientation has been established experimentally, the model will suggest additional distance measurements that will be necessary to pin down the receptor s intracellular loops onto the surface of the G protein. Proceeding in such an iterative fashion should provide the experimental evidence that is critically important in refining the current models of the receptor—G protein complex. 

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