The profile also indicates that direct transition of F 1 conformer to F 4 would encounter an energetic barrier of 9.8 kcal mol -1 ; this compares with barriers of 4.6 and 7.9 kcal mol -1 for the indirect route via F 2/3 intermediates; this indeed corresponds to the F 1 → F 4 route observed from the triplicate 10 s unbiased MD simulations.