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Title: The nest/egg motif in proteins - a comprehensive structural bioinformatics study
P117
Pal, Debnath; Suehnel, Juergen; Weiss, Manfred S.

dpal@imb-jena.de, jsuehnel@imb-jena.de, msweiss@embl-hamburg.de
Institute of Molecular Biotechnology, Jena Centre for Bioinformatics, Beutenbergstr. 11, D-07745 Jena / Germany and EMBL Hamburg Outstation, c/o DESY, Notkestr. 85. D-22603 Hamburg / Germany

The main-chain conformations of protein chains can be conveniently analyzed by means of the Ramachandran map displaying the distribution of amino acid backbone torsional angles phi and psi [1]. The interpretation of Ramachandran maps usually focuses on clusters for specific secondary structure elements such as beta-sheets and different helix types. In these cases the main-chain conformations of successive amino acid pairs are identical or at least similar.

Recently, Watson and Milner-White have discovered that many anion and cation binding sites (where anions and cations can be any atoms exhibiting a full or a partial negative and positive charge, respectively) in proteins are made up by a sequence of three amino acids of which two exhibit "enantiomeric" main-chain conformations. The term "enantiomeric" refers to the fact that, contrary to the conformations in beta-sheets and helices, the main-chain torsional angles (phi,psi) of the two adjacent amino acids are approximately inverted about the center of the Ramachandran map. The authors have called this motif a nest because three successive residues obeying this torsional angle criterion form a concave depression which can serve as a binding site for an atom or a group of atoms with a full or partial negative charge [2,3]. In the majority of cases, the nests do bind to an atom or a group of atoms, which we suggest may, as a binding partner of a "nest", be descriptively and conveniently called "egg" [4].
It is intriguing that many structural motifs described previously, such as Schellman loops, the oxyanion holes of serine proteases, P-loops in ATP- or GTP-binding proteins can be subsumed under this nest/egg-concept. If dipeptides with different enantiomeric main-chain torsional angle combinations are considered, the nest/egg-concept can even be extended to cation binding sites although the experimental evidence for this is not as ample as for the anion-binding nests [2,3].

Watson and Milner-White conducted their analysis on a limited data base of 67 protein structures [2,3]. We have performed an extended analysis of their concept in a data base about 20 times larger [4] (the same database as the one used in reference [5]). It turns out that some of the results obtained by Watson and Milner-White are confirmed, others have to be modified and some new aspects are unveiled as well. For example, detailed information on the amino acid occurrence in nests and the nest occurrence in secondary structure elements is reported. Moreover, a thorough analysis of the egg occupancy of nests is presented.

The nest/egg concept described here takes ligands, cofactors, water molecules, etc. into account and therefore sets the stage to a general approach to binding sites in proteins. Furthermore, it should also be of importance to other aspects of protein structure analysis and prediction. A preliminary analysis has shown that the nest motif is only one example of a more comprehensive list of non-repetitive main-chain dipeptide conformations. Finally, one may speculate whether these motifs may constitute stable structures very early along the pathway of folding since they are inherently local structures and thus would not require a large entropy reduction upon formation.
[1] G. N. Ramachandran, V. Sasisekharan, Adv. Prot. Chem. 1968, 23, 293-437.
[2] J. D. Watson, E. J. Milner-White, J. Mol. Biol. 2002, 315, 187-198.
[3] J. D. Watson, E. J. Milner-White, J. Mol. Biol. 2002, 315, 199-207.
[4] D. Pal, J. Sühnel, M. S. Weiss, Angew. Chem. Int. Ed. in press.
[5] M. Brandl, M. S. Weiss, A. Jabs, J. Sühnel, R. Hilgenfeld, J. Mol. Biol. 2001, 307, 357-377.