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The dominant role of side-chain backbone interactions in structural realization of amino acid code. ChiRotor: A side-chain prediction algorithm based on side-chain backbone interactions

Accelrys, Inc., San Diego, California 92121, USA

(RECEIVED July 16, 2006; FINAL REVISION November 10, 2006; ACCEPTED November 13, 2006)

The basic differences between the 20 natural amino acid residues are due to differences in their side-chain structures. This characteristic design of protein building blocks implies that side-chain–side-chain interactions play an important, even dominant role in 3D-structural realization of amino acid codes. Here we present the results of a comparative analysis of the contributions of side-chain–side-chain (s-s) and side-chain–backbone (s-b) interactions to the stabilization of folded protein structures within the framework of the CHARMm molecular data model. Contrary to intuition, our results suggest that side-chain–backbone interactions play the major role in side-chain packing, in stabilizing the folded structures, and in differentiating the folded structures from the unfolded or misfolded structures, while the interactions between side chains have a secondary effect. An additional analysis of electrostatic energies suggests that combinatorial dominance of the interactions between opposite charges makes the electrostatic interactions act as an unspecific folding force that stabilizes not only native structure, but also compact random conformations. This observation is in agreement with experimental findings that, in the denatured state, the charge–charge interactions stabilize more compact conformations. Taking advantage of the dominant role of side-chain–backbone interactions in side-chain packing to reduce the combinatorial problem, we developed a new algorithm, ChiRotor, for rapid prediction of side-chain conformations. We present the results of a validation study of the method based on a set of high resolution X-ray structures.

Keywords: protein structure; protein folding; amino acid code; side-chain prediction; electrostatic interactions; van der Waals interactions

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