An automatic homology modeling method consisting of database searches and simulated annealing

We introduce a method of homology modeling consisting of database searches and simulated annealing. All processes involving searches for homologous proteins, alignment, the construction of Calpha atoms, construction of main-chain atoms, and the construction of side-chain atoms are performed automatically. In this method, main-chain conformations are generated from the weighted average of mainchain coordinates in reference proteins. The weight is defined by the local space homology representing the similarity of environmental residues at topologically equivalent positions in reference proteins. Side-chain conformations are generated for constructed main-chain atoms by database searches, and main-chain atoms are optimized for the fixed side-chain conformations. These two processes, i.e., the side-chain generation and main-chain optimization, are repeated several times. This type of construction provides a structure similar to the x-ray structure, in particular, for main-chain and side-chain atoms in the residues belonging to structurally conserved regions (SCRs). The accuracy of our method was evaluated for 14 proteins whose structures are known. The average root mean square deviation between models and x-ray structures was 2.29 A for all atoms, and the percentage of chi1 angles within 30 degrees was 72.6% for SCRs residues. Some models were in good agreement with their respective x-ray structures. Our method, which has the advantage of being automated, gives results similar to, or better than, published results for three widely used test proteins. Our software, FAMS, is available on the World Wide Web.