The detection of remote homologies is of major importance for molecular biology ap- plications like drug discovery. The problem is still very challenging even for state-of-the-art probabilistic models of protein families, namely Profile HMMs. In order to improve re- mote homology detection we propose feature based semi-continuous Profile HMMs. Based on a richer sequence representation consisting of features which capture the biochemical properties of residues in their local context, family specific semi-continuous models are estimated completely data-driven. Additionally, for substantially reducing the number of false predictions an explicit rejection model is estimated. Both the family specific semi- continuous Profile HMM and the non-target model are competitively evaluated. In the experimental evaluation of superfamily based screening of the SCOP database we demonstrate that semi-continuous Profile HMMs significantly outperform their discrete counterparts. Using the rejection model the number of false positive predictions could be reduced substantially which is an important prerequisite for target identification applica- tions.
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