There are two approaches, exhaustive and heuristic approaches, used in multiple sequence alignment. The exhaustive alignment method includes searching all possible aligned positions simultaneously. This is the best algorithm to find the best or exact solution for a particular problem by examining all mathematical combinations.

For discrete problems in which no efficient solution method is known, it might be necessary to test each possibility sequentially in order to determine if it is the solution. Such exhaustive examination of all possibilities is known as exhaustive search, direct search, or the “brute force” method. Unless it turns out that NP-problems are equivalent to P-problems, which seems unlikely but has not yet been proved, NP-problems can only be solved by exhaustive search in the worst case.

Similar to dynamic programming in pairwise alignment, which involves the use of a two-dimensional matrix to search for an optimal alignment, to use dynamic programming for multiple sequence alignment, extra dimensions are needed to take all possible ways of sequence matching into consideration. This means to create a multidimensional search matrix. For example, for three sequences, a three-dimensional matrix is required to account for all possible alignment scores. Back-tracking is applied through the three-dimensional matrix to find the highest scored path that represents the optimal alignment. For aligning N sequences, an N-dimensional matrix is needed to be filled with alignment scores. As the amount of computational time and memory space required increases exponentially with the number of sequences, it makes the method computationally prohibitive to use for a large data set. For this reason, full dynamic programming is limited to small datasets of less than ten short sequences. For the same reason, few multiple alignment programs employing this “brute force” approach are publicly available.

DCA (Divide-and-Conquer Alignment is a web-based program that is in fact semi-exhaustive because certain steps of computation are reduced to heuristics. It works by breaking each of the sequences into two smaller sections. The breaking points are determined based on regional similarity of the sequences. If the sections are not short enough, further divisions are carried out. When the lengths of the sequences reach a predefined threshold, dynamic programming is applied for aligning each set of subsequences. The resulting short alignments are joined together head to tail to yield a multiple alignment of the entire length of all sequences. This algorithm provides an option of using a more heuristic procedure (fastDCA) to choose optimal cutting points so it can more rapidly handle a greater number of sequences. It performs global alignment and requires the input sequences to be of similar lengths and domain structures. Despite the use of heuristics, the program is still extremely computationally intensive and can handle only datasets of a very limited number of sequences.