Protein topology prediction through constraint-based search and the evaluation of topological folding rules

An algorithm for predicting protein alpha/beta-sheet topologies from secondary structure and topological folding rules (constraints) has been developed and implemented in Prolog. This algorithm (CBS1) is based on constraint satisfaction and employs forward pruned breadth-first search and rotational invariance. CBS1 showed a 37-fold increase in efficiency over an exhaustive generate and test algorithm giving the same solution for a typical sheet of five strands whose topology was predicted from secondary structure with four topological folding constraints. Prolog specifications of a range of putative protein folding rules were then used to (i) replicate published protein topology predictions and (ii) validate these rules against known protein structures of nucleotide-binding domains. This demonstrated that (i) manual techniques for topology prediction can lead to non-exhaustive search and (ii) most of these protein folding principles were violated by specific proteins. Various extensions to the algorithm are discussed.