Assignment of polar states for protein amino acid residues using an interaction cluster decomposition algorithm and its application to high resolution protein structure modeling.

We have developed a new method (Independent Cluster Decomposition Algorithm, ICDA) for creating all-atom models of proteins given the heavy-atom coordinates, provided by X-ray crystallography, and the pH. In our method the ionization states of titratable residues, the crystallographic mis-assignment of amide orientations in Asn/Gln, and the orientations of OH/SH groups are addressed under the unified framework of polar states assignment. To address the large number of combinatorial possibilities for the polar hydrogen states of the protein, we have devised a novel algorithm to decompose the system into independent interacting clusters, based on the observation of the crucial interdependence between the short range hydrogen bonding network and polar residue states, thus significantly reducing the computational complexity of the problem and making our algorithm tractable using relatively modest computational resources. We utilize an all atom protein force field (OPLS) and a Generalized Born continuum solvation model, in contrast to the various empirical force fields adopted in most previous studies. We have compared our prediction results with a few well-documented methods in the literature (WHATIF, REDUCE). In addition, as a preliminary attempt to couple our polar state assignment method with real structure predictions, we further validate our method using single side chain prediction, which has been demonstrated to be an effective way of validating structure prediction methods without incurring sampling problems. Comparisons of single side chain prediction results after the application of our polar state prediction method with previous results with default polar state assignments indicate a significant improvement in the single side chain predictions for polar residues. (c) 2006 Wiley-Liss, Inc.