Abstract Summary: Recent development of strategies using multiple sequence alignments (MSA) or profiles to detect remote homologies between proteins has led to a significant increase in the number of proteins whose structures can be generated by comparative modeling methods. However, prediction of the optimal alignment between these highly divergent homologous proteins remains a difficult issue. We present a tool based on a generalized Viterbi algorithm that generates optimal and sub-optimal alignments between a sequence and a Hidden Markov Model. The tool is implemented as a new function within the HMMER package called hmmkalign. Availability: http://www-spider.cea.fr/Groups/hk3039/view.html Supplementary information: Supplementary data are available at Bioinformatics online.

MOTIVATION: Human Nbs1 and its homolog Xrs2 in Saccharomyces cerevisiae are part of the conserved MRN complex (MRX in yeast) which plays a crucial role in maintaining genomic stability. NBS1 corresponds to the gene mutated in the Nijmegen breakage syndrome (NBS) known as a radiation hyper-sensitive disease. Despite the conservation and the importance of the MRN complex, the high sequence divergence between Nbs1 and Xrs2 precluded the identification of common domains downstream of the N-terminal Fork-Head Associated (FHA) domain. RESULTS: Using HMM-HMM profile comparisons and structure modelling, we assessed the existence of a tandem BRCT in both Nbs1 and Xrs2 after the FHA. The structure-based conservation analysis of the tandem BRCT in Nbs1 supports its function as a phosphoserine binding domain. Remarkably, the 5 bp deletion observed in 95% of NBS patients cleaves the tandem at the linker region while preserving the structural integrity of each BRCT domain in the resulting truncated gene products.