HHblits: lightning-fast iterative protein sequence searching by HMM-HMM alignment

HHblits is a protein sequence search tool that works by iterative pairwise comparison of profile hidden Markov models. It outperforms existing tools in terms of speed, sensitivity and alignment quality. Sequence-based protein function and structure prediction depends crucially on sequence-search sensitivity and accuracy of the resulting sequence alignments. We present an open-source, general-purpose tool that represents both query and database sequences by profile hidden Markov models (HMMs): 'HMM-HMM–based lightning-fast iterative sequence search' (HHblits; http://toolkit.genzentrum.lmu.de/hhblits/ ). Compared to the sequence-search tool PSI-BLAST, HHblits is faster owing to its discretized-profile prefilter, has 50–100% higher sensitivity and generates more accurate alignments.