Energy minimization calculations were used to generate secondary structures of partial and full-length myotonic dystrophy messenger RNAs (DMPK mRNAs) carrying variable numbers of CUG triplet repeats (n = 0 to 500). The results suggest that (1) unitary hairpins are the most stable structures formed; (2) long-axis distances of unfolded hairpins are directly proportional to CUG repeat numbers; and (3) hairpins composed of CUG repeats might form interstem clusters that are stabilized by hydrogen or ionic bonds. A model is proposed whereby DMPK mRNAs are sterically impeded from transport through nuclear pores, by giant hairpins or hairpin clusters formed by CUG repeats above a limit size (n > or = 44).