Protein Sequence Threading, the Alignment Problem and a Two Step Strategy

Conventionally, protein structure prediction via "threading" relies on some non-optimal method to align a protein sequence to each member of a library of known structures. We show how a score function (force field) can be modified so as to allow the direct application of a dynamic programming algorithm to the problem. This is involves an approximation whose damage can be minimised by an optimisation process during score function parameter determination. The method is compared to sequence to structure alignments using a more conventional pair-wise score function and the frozen approximation. The new method produces results comparable to the frozen approximation, but is faster and has fewer adjustable parameters. It is also free of memory of the template's original amino acid sequence and does not suffer from a problem of non-convergence which can be shown to occur with the frozen approximation. Alignments generated by the simplified score function can then be ranked using a second score..