What is the value added by human intervention in protein structure prediction?

This article presents results of blind predictions submitted to the CASP4 protein structure prediction experiment. We made two sets of predictions: one using the fully automated SAM-T99 server and one using the improved SAM-T2K method with human intervention. Both methods use iterative hidden Markov model-based methods for constructing protein family profiles, using only sequence information. Although the SAM-T99 method is purely sequence based, the SAM-T2K method uses the predicted secondary structure of the target sequence and the known secondary structure of the templates to improve fold recognition and alignment. In this article, we try to determine what aspects of the SAM-T2K method were responsible for its significantly better performance in the CASP4 experiment in the hopes of producing a better automatic prediction server. The use of secondary structure prediction seems to be the most valuable single improvement, though the combined total of various human interventions is probably at least as important.