If I understand your question correctly, then I think for case of pairwise alignment, there is a simple explanation. I believe the key insight is that: *a mismatch should always score better than a gap (opening)*. This follows biologically since the insertion/deletion (indel) rate is roughly 1/10th that of the substitution rate (i.e. the occurrence of single nucleotide changes), at least in vertebrates. (This varies across the tree of life but I think the substitution rate virtually always exceeds the indel rate.) To understand why this matters, consider an example: ATG-AG ATGT-G This is an 'impossible alignment' under the probabilities you gave since here we have a transition from a gap-residue alignment to a residue-gap. However, under our assumption that mismatches are more likely biologically than indels, the correct alignment should be: ATGAG ATGTG Indeed, the latter does look like a better alignment. This also follows for more complex examples, so this: ATG--AAG ATGTT-AG Becomes this: ATG-AAG ATGTTAG (Or this: ATGA-AG ATGTTAG )