taking into consideration geometrical and steric constraints. One of the greatest concerns in nucleic acid design is ensuring that the target structure has the lowest free energy (i.e. is the most thermodynamically favorable) whereas misformed structures have higher values of free energy and are thus unfavored. These goals can be achieved through the use of a number of approaches, including heuristic, thermodynamic, and geometrical ones. Almost all nucleic acid design tasks are aided by computers, and a number of software packages are available for many of these tasks. Two considerations in nucleic acid design are that desired hybridizations should have melting temperatures in a narrow range, and any spurious interactions should have very low melting temperatures (i.e. they should be very weak). There is also a contrast between affinity-optimizing "positive design", seeks to minimize the energy of the desired structure in an absolute sense, and specificity-optimizing "negative design", which considers the energy of the target structure relative to those of undesired structures. Algorithms which implement both kinds of design tend to perform better than those that consider only one type. Approaches Heuristic methods Heuristic methods use simple criteria which can be quickly evaluated to judge the suitability of different sequences for a given secondary structure. They have the advantage of being much less computationally expensive than the energy minimization algorithms needed for thermodynamic or geometrical modeling, and being easier to implement, but at the cost of being less rigorous than these models. Sequence symmetry minimization is the oldest approach to nucleic acid design and was first used to design immobile versions of branched DNA structures. Sequence symmetry minimization divides the nucleic acid sequence into overlapping subsequences of a fixed length, called the criterion length. Each of the 4N possible subsequences of length N is allowed to appear only once in the sequence. This ensures that no undesired hybridizations can occur which have a length greater than or equal to the criterion length. A related heuristic approach is to consider the "mismatch distance", meaning the number of positions in a certain frame where the bases are not complementary. A greater mismatch distance lessens the chance that a strong spurious interaction can happen. This is related to the concept of Hamming distance in information theory. Another related but more involved approach is to use methods from coding theory to construct nucleic acid sequences with desired properties. Thermodynamic models Information about the secondary