Possible origins of V617X mutational effects derived from the snapshots of various mutant simulations at 44 ns. Color codes are the same as in Figure 1. In wild-type JAK2 (WT), the JH1 activation loop is in contact with V617 and nearby residues, as well as the residues of the JH2 C-helix (especially F595 and S591). V617C is very similar to WT. All key interactions seem to be kept. However, C617 binds to different parts of the JH1 activation loop: it is now close to K1005 rather than L1001 and P1002. K1005 is the edge of the red region shown in the figure. V617I is similar to V617C and WT in that I-2 and I-3 are maintained (i.e., the JH1 activation loop is locked by the JH2 C-helix and residues in the V617 region). However, the bulky side chain of I617 pushes the JH1 activation loop toward the I-1 interface (JH1 C-helix/JH2 C-helix) and breaks the I-1 interactions. In V617F, F617 interacts with F595 and hence blocks the contacts between the JH1 activation loop and the JH2 C-helix. The JH1 activation loop is wide-open and highly accessible. In V617Y, Y617 also interacts with F595 and blocks the contacts between the JH1 activation loop and the JH2 C-helix. However, the polar tail of Y617 moves near the interface between the JH1 C-helix and the JH2 C-helix, forming multiple hydrogen-bonds with nearby water molecules and the JH1 activation loop (not shown). The result is that the JH1/JH2 interface is not as open as in the case of V617F.