Metadynamics studies of 1a/1b (quinoline oligoamide pentamers substituted by β-pinene-
Figure 1. The free-energy profile of 1a Figure 2. The structure of 1a
derived pyridyl amine at C-terminal) indicated the same helical bias as the experimental results. 1a possesses a (R) –β -pinene-derived pyridyl amine (Figure 1 right), yields a P helix as the global minimum. From the free-energy profile (FEP) of1a , it can see that P helix has about 2.3 kcalmol-1 minima free energy. The free-energy of M helix is 3.7 kcalmol-1 in 1a , the energy gap is 1.4 kcalmol-1, so the helical selectivity of 1a is not obvious. And 1b has the same case,for 1b (enantiomer of 1a ), the M helix are more stable than P helix. 1b possesses a (S) –β -pinene-derived pyridyl amine (Supporting Information S1), yields an M helix as the global minimum, and minimum energy is about 2.08 kcalmol-1. The free-energy of P helix is 3.5 in 1b. Therefore, the helix handedness of1a/1b is mainly induced by the carbon atomic chirality ofβ -pinene-derived pyridyl amine. The structural features of the (P)−1a /(M)−1b were conducted by extracting conformations from the M-and P-helix using the 400 ns metadynamics trajectories. From the most stable structure of 1a and1b (Supporting Information S2), it can get following structural parameters. The helical pitch of 1a and 1b is 3.5 Å and 3.6 Å. The terminal group (β ‑pinene-derived pyridyl amine) did not form any hydrogen bonds with quinoline oligoamide. That is, the hydrogen bond can not affect the helical handedness in1a/1b . Based on the analysis of the stable conformations of1a/1b , the two methyl groups of β ‑pinene both rotate to the out of helix, which can decrease the steric hindrance. Thus, the different between P and M is only from the angle degree of ∠NQ−CQ−C−NA (figure 1 right) and ∠CQ−CQ−NA−C. The figure 3 shows the structural analysis of 1a . From Figure 3, it can see that the angle peaks of ∠NQ−CQ−C−NA lie at ±17° and ∠CQ−CQ−NA−C lies at ±180° for 1a . The frequency of occurrence of ∠NQ−CQ−C−NA is bigger than that of ∠CQ−CQ−NA−C, it is revealed that the ∠NQ−CQ−C−NA obviously determined the helix bias sense of foldamer. From Figure 4 , it can see that the angle
Figure 3. Dihedral angle distributions of 1a Figure 4.The frequency of occurrence for
∠NQ−CQ−C−NA in1a and 1b
peaks of ∠NQ−CQ−C−NA are 17° in P-1a and P-1b , and it is -17° in M-1aand M-1b. It means∠NQ−CQ−C−NA do significantly influence the helix handedness of foldamer. Because there is not formation of hydrogen bond between the terminal group and quinoline oligoamide, the steric hindrance effect and chiral atom should be the important factors on the helix handedness of 1a/1b .
2.2. Helix handedness of β-pinene-derived pyridyl amine substituted oligomers 2a/2b at C-terminal
To find the proof of hydrogen bonds on the helix-sense bias of foldamer, Zheng [9] et al had synthesized the other foldamer 2 , in foldamer 2 , hydrogen bond O–H−NA is formed between terminal group and quinoline-based amine (Figure 5). However, they found that the hydrogen bond O–H−NA cannot enhance the helix-sense bias of foldamer. So we built foldamer2 according to the experimental data and performed the dynamic calculation. From the results of metadynamics calculations, it can see that free-energy of 2a (Supporting information S3) and2b only has little change compared to 1a and1b , 2b shows M helix with the global minimum, the minimum free-energy is about 2.47 kcalmol-1 (Figure 6 ). And the free-energy gap of M and P is 2.1 kcalmol-1in 2b . The structural parameters of2a/2b are similar to those of 1a/1b . The helical pitch of 2a and 2b is 3.62 and 3.56Å, and the R chirality ofβ -pinene still induces a P helix, and S chirality induces the M helix in 2b (Supporting information S4). Due to the similar structural parameters and free-energy gap between 1a/1b and 2a/2b , it means that the hydrogen bond O–H−NA does not obviously improve the selection of foldamer 2a/2b .