APPLICATION OF A DIRECTED CONFORMATIONAL SEARCH FOR GENERATING 3-D COORDINATES FOR PROTEIN STRUCTURES FROM ALPHA-CARBON COORDINATES

A directed conformational search algorithm using the program CONGEN (ref. 3), which samples backbone conformers, is described. The search technique uses information from the partially built structures to direct the search process and is tested on the problem of generating a full set of backbone Cartesian coordinates given only alpha-carbon coordinates. The method has been tested on six proteins of known structure, varying in size and classification, and was able to generate the original backbone coordinates with RMSs ranging from 0.30-0.87 angstrom for the alpha-carbons and 0.5-0.99 angstrom RMSs for the backbone atoms. Cis peptide linkages were also correctly identified. The procedure was also applied to two proteins available with only alpha-carbon coordinates in the Brook-haven Protein Data Bank; thioredoxin (SRX) and triacylglycerol acylhydrolase (TGL). All-atom models are proposed for the backbone of both these proteins. In addition, the technique was applied to randomized coordinates of flavodoxin to assess the effects of irregularities in the data on the final RMS. This study represents the first time a deterministic conformational search was used on such a large scale.