NSD1 is a SET-domain histone methyltransferase that methylates lysine 36 of histone 3. In the crystal structure of NSD1, the post-SET loop is in an autoinhibitory position that blocks binding of the histone peptide as well as the entrance to the lysine-binding channel. The conformational dynamics preceding histone binding and the mechanism by which the post-SET loop moves to accommodate the target lysine is currently unknown, although potential models have been proposed. Using molecular dynamics simulations, we have identified potential conformations of the post-SET loop differing from those of previous studies, as well as proposed a model of peptide-bound NSD1. Our simulations illustrate the dynamic behavior of the post-SET loop and the presence of a few distinct conformations. In every case, the post-SET loop remains in an autoinhibitory position blocking the peptide-binding cleft, suggesting that another interaction is required to optimally position NSD1 in an active conformation. This finding provides initial evidence for a mechanism by which NSD1 preferentially binds nucleosomal substrates.