Xa ll Li JL A Y2 12 iff

pepOall

+H3N

Fig. 6.6 Sequences of the four b 3-depsi-peptides and the b3-peptide considered in Fig. 6.5. b-peptide pepOnone: H-b-HVal-b-HAla-b-HLeu-b-HAla(a-Met)-b-HVal-b-HAla-b-HLeu-OH. b-depsipeptide pepO2: H-b-HVal-b-dHAla-b-HLeu-b-HVal-b-HAla-b-HLeu-b-HVal-OH; b-depsipeptide pepO4: H-b-HAla-b-HLeu-b-HVal-b-dHAla-b-HLeu-b-HVal-b-HAla-OH; b-depsipeptide pepO6: H-b-HAla-b-

HLeu-b-HVal-b-HVal-b-HLeu-b-dHAla-b-HVal-OH; b-depsipeptide pepOall: H-b-HVal-b-dHAla-b-dHLeu-b-dHVal-b-dHAla-b-dHLeu-b-dHVal-OH; The N-terminal amino- and C-terminal carboxylate groups are both protonated in the simulations as suggested by the experimental data. The depsi-amino acids are denoted with dHAla, dHVal, dHLeu.

a-position prevents helix formation [19], whereas substitution of hydroxyl groups at the a-positions in conjunction with standard side chains at the b-positions leads to the formation of a (P)2.512 helix [36]. The influence of different stereocenters (SR versus SS) in the backbone of a Val-Phe b-peptide on its conformational preferences was found to be significant, both in simulation and in NMR experiments [37]. Also for carbopeptoids the presence of cis versus trans linkage across the tetrahydrofuran ring influences the emergence of a particular fold [30, 31]. Whether the presence of side chains with a branching point adjacent to the b-carbon in the backbone (e.g. Ile or Val) [38] or the presence of polar or charged side chains, which would be able to form salt bridges [25, 26], would enhance helix formation in b-peptides was also investigated.

Use of an explicit representation of solvent in the simulations offers the possibility of investigating solvent effects upon fold formation. b-Peptides of different chain lengths that adopt helical folds in methanol, show less to no tendency to do so when solvated in water [25, 26, 39]. Solvation in chloroform tends to enhance helix formation [33, 40]. For a-peptides, b-hairpin formation in water has been observed [16, 41]. In less polar solvents, such as DMSO, partial helix formation could be observed for a particular 8-a-peptide [42]. Carbopeptoids also showed different folding behavior in DMSO versus chloroform [30, 31]. The observed effects can be rationalized in terms of degree of solvent polarity or dielectric permittivity and competitiveness to form solute-solvent hydrogen bonds. For an example of the complex effects of the addition of co-solvent upon hydrophobic association we refer to [43].

Convergence of the Simulated Folding Equilibrium

The convergence of a folding equilibrium can be monitored by calculating the number of conformational clusters in a MD trajectory as function of time. A conformational cluster is defined as the set of solute trajectory structures that deviate less than a given limit from each other. Figure 6.7 shows for example trajectory structures of the 7-b-peptide for which the backbone atom-positional root-mean-square deviation (RMSD) for residues 2-6 from the central member structure of the cluster is less than 0.09 nm. The clustering RMSD criteria chosen, 0.09 nm in

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