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accomplish this, the strands of the parent molecule must separate to provide access to these templates.

The regulation of important physiological processes is extremely precise and complex. In addition to many other layers of control, the strand separations required for specific functions must be carefully regulated to occur at the precise positions needed for each activity, and only at times when that activity is to be initiated. Because DNA prefers to remain in the B-form under normal conditions, strand separation requires the expenditure of (free) energy. The energy required for strand separation depends upon the sequence of base pairs being separated. Because A·T base pairs are held by only two hydrogen bonds whereas G·C pairs are held by three, it is energetically less costly to separate the former pairs than the latter. For this reason, strand separations tend to be concentrated in A+T-rich regions of the DNA. As we will see in this chapter, this provides the sequence dependence necessary to control the sites of separation.

Controlling the occurrence of separations can be accomplished by modulating the amount of energy stored in the DNA molecule itself. This is done by changing the topological constraints on the molecule. DNA in living organisms is topologically constrained into domains within which the linking number is fixed. Enzymes can change this linking number, placing the DNA in a higher energy state in which pure B-form DNA is less favored and partial strand separation is thermodynamically more achievable. (The topology and geometry of superhelicity, which is the jargon name for this process, have been described by White in Chapter 6.)

In order to illuminate the role of strand separation in DNA functions, one needs accurate theoretical methods for predicting how a particular DNA sequence will behave as its linking number is varied. This chapter describes methods that have been developed to make such predictions. The results of sample calculations are shown, and the insights that they provide regarding specific DNA activities are sketched. The global and topological nature of the constraints imposed on DNA causes behavior that exhibits many unusual and surprising features.

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