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Aligning protein sequences using a score matrix has became a routine but valuable method in modern biological research. However, alignment in the 'twilight zone' remains an open issue. It is feasible and necessary to construct a new score matrix as more protein structures are resolved. Three structural class-specific score matrices (all-alpha, all-beta and alpha/beta) were constructed based on the structure alignment of low identity proteins of the corresponding structural classes. The class-specific score matrices were significantly better than a structure-derived matrix (HSDM) and three other generalized matrices (BLOSUM30, BLOSUM60 and Gonnet250) in alignment performance tests. The optimized gap penalties presented here also promote alignment performance. The results indicate that different protein classes have distinct amino acid substitution patterns, and an amino acid score matrix should be constructed based on different structural classes. The class-specific score matrices could also be used in profile construction to improve homology detection.

Aligning protein sequences using a score matrix has became a routine but valuable method in modern biological research. However, alignment in "Twilight Zone" is still a challenging issue. New score matrices such as Position Specific Score Matrix and structural context-based matrix have been issued to deal with it, whereas generalized matrices are still useful in pairwise alignment and/or some steps of generating profiles. Family-specific matrices have been proved effective in improving alignment, whereas the generalization of them is reduced. ALPHASUM, a score matrix based on structure alignment of low identity all-alpha proteins is constructed. Performance comparison suggests substitution pattern difference between all-alpha proteins and all proteins and indicates that alignment of all-alpha proteins in "Twilight Zone" can be improved by using alpha class-specific matrix and gap penalties. The implication between structure-derived matrix and influence of amino acid substitution to structure is also suggested.

Sequence alignment has been a most commonly used method in modern biological research. However, sequence alignment in "Twilight Zone" is still a challenging issue. Three protein class-specific matrices are constructed to investigate whether alignment in "Twilight Zone" can be improved by using class-specific matrices and gap penalties. The substitution pattern differences between different protein classes do improve the performances of the three class-specific matrices. Analyzing amino acids substitution pattern based on different matrices also suggests important information for protein sequence design.