Clusters in alpha/beta barrel proteins: Implications for protein structure, function, and folding: A graph theoretical approach

The alpha/beta barrel fold is adopted by most enzymes performing a variety of catalytic reactions, but with very low sequence similarity. In order to understand the stabilizing interactions important in maintaining the alpha/ beta barrel fold, we have identified residue clusters in a dataset of 36 al pha/beta barrel proteins that have less than 10% sequence identity within t hemselves, A graph theoretical algorithm is used to identify backbone clust ers. This approach uses the global information of the nonbonded interaction in the alpha/beta barrel fold for the clustering procedure. The nonbonded interactions are represented mathematically in the form of an adjacency mat rix. On diagonalizing the adjacency matrix, clusters and cluster centers ar e obtained from the highest eigenvalue and its corresponding vector compone nts. Residue clusters are identified in the strand regions forming the beta barrel and are topologically conserved in all 36 proteins studied. The res idues forming the cluster in each of the alpha/beta protein are also conser ved among the sequences belonging to the same family. The cluster centers a re found to occur in the middle of the strands or in the C-terminal of the strands. In most cases, the residues forming the clusters are part of the a ctive site or are located close to the active site. The folding nucleus of the alpha/beta fold is predicted based on hydrophobicity index evaluation o f residues and identification of cluster centers. The predicted nucleation sites are found to occur mostly in the middle of the strands. (C) 2001 Wile y Liss, Inc.