Computational Approaches in Peptide and Protein Design: An Overview - Peptide and Protein Design for Biopharmaceutical Applications - page 15

represented with MM [27,28]. This approach was applied to Ac-Ala-
OMe and showed excellent consistency with the experimental data in
Figure 2.1(e) [1]. Specifically, the molecule of Ac-Ala-OMe was treated
with the fast approximate QM method SCCDFTB [29], whereas inter-
actions between Ac-Ala-OMe and the explicit water molecules were
calculated either with SCCDFTB (electrostatic interactions) or with
force fields with flexible valence geometry (such as AMBER).
Interactions between the water molecules were calculated with the
same force fields. Figure 2.2(a) presents the results of sampling over-
lapped with contours corresponding (from purple to pink) to 99.8%,
99.5%, 98%, 95% and 90% of the levels of the experimental distribu-
tion of the (f, c) points for the alanine residues from the experimental
distribution in Figure 2.1(e). Distribution of sampled conformations in
Figure 2.2(a) is remarkably close to that in Figure 2.1(e). All main
regions of the experimental distributions have comparable relative
populations, including the pass zone. Also, the diagonal shapes of dis-
tributions in the alpha R and alpha L regions are reproduced, whereas
only a few conformations appear in the region of the (f, c) values
around ( 60-30, 150-30). One slight discrepancy is the rela-
tively low population of the narrow zone around c 100.

180

beta

alpha R

pass

ψ 0

alpha R

-180

-180 0 180 -180 0 180

φ φ

2(a) 2(b)

Figure 2.2 (a) Sampled conformational distribution of Ac-Ala-OMe obtained with
the QM/MM approach. Lines show 99.8%, 99.5%, 98%, 95% and 90% (from
purple to pink) levels of the experimental distribution of the (f, c) points for alanine
residues (adapted from [1], Figure 6). (b) Ramachandran map of free energy for
Ac-Ala-OMe in water, obtained with the AMOEBA polarizable force field. Lines
show energy levels of 3.2, 2.8, 2.4, 2.0, 1.6, 1.2, 0.8 and 0.4 kcal/mol, from red to
dashed orange (map courtesy of Prof. Jay Ponder). Adapted with permission from
John Wiley & Sons, Inc (see colour Plate 1)