Furthermore, the triazole ring has a large dipole that could align with that of the other amides in a given peptide secondary structure. 7 In addition to the amide NH and carbonyl groups flanking the residue, the triazole ring possesses two nitrogen atoms (N 2 and N 3) that might act as hydrogen bond acceptors. The backbone of the ε-amino acid is one atom longer as compared to that of a native dipeptide ( Figure 1a), leading to a calculated increase in C α-C αspacing of 1.1 Å. 6 We hypothesized that the structural and functional features of the triazole ε 2-amino acids could also be potentially useful in the context peptide and protein secondary structures. 5 We reported recently the use of triazole ε 2-amino acids as a dipeptide replacement in the design of selfassembling peptide nanotubes. The reactivity and functional group tolerance of Cu(I) catalyzed 1,3-dipolar cycloaddition between azides and alkynes to give 1,2,3-triazoles 4 have led to the increasing use of this reaction in bioconjugate chemistry. Simul.(a) A native dipeptide and the L-leucine derived triazole-ε 2- amino acid incorporated as a replacement (b) Sequences for GCN4-pLI and modified peptides 1- 3 X denotes incorporation of the ε 2-residue. Hermans, inIntermolecular Forces, edited by B. (94)00397-1, Google Scholar Crossref, ISI (71)90324-X, Google Scholar Crossref, ISI Part II: The Role of Water in Protein Folding, Self-Assembly and Molecular Recognition ( World Scientific, Singapore, 2010). Ben-Naim, Molecular Theory of Water and Aqueous Solutions. (94)00048-4, Google Scholar Crossref, ISI
PEPTIDE BACKBONE FREE
This correlation however is weak for the overall solvation free energies owing to the fact that the cavity and dispersion free energy contributions are almost exactly cancelling each other. The cavity and dispersion interaction contributions correlate quite well with the solvent accessible surface area of the nonpolar side chains attached to the backbone. We find that cavity formation next to the peptide backbone is entropically favored over formation of similar sized nonpolar side chain cavities in bulk water, in agreement with earlier work in the literature on analysis of cavity fluctuations at nonpolar molecular surfaces. The solvation free energies of nonpolar side chains have been furthermore decomposed into a repulsive cavity formation contribution and an attractive dispersion free energy contribution. This results in a very small unfavorable free energy cost, or even free energy gain, of solvating the nonpolar side chains in strong contrast to solvation of small hydrophobic or nonpolar molecules in bulk water. We find that a similar compensation does not apply to the nonpolar side chains while the backbone greatly reduces the unfavorable solvation entropies, the solvation enthalpies are either more favorable or only marginally affected. The observed differences are large however, owing to a nearly perfect enthalpy-entropy compensation, the solvation free energies of polar side chains remain largely unaffected by the peptide backbone. The solvation entropies and enthalpies of the polar side chains are negative, but in absolute magnitude smaller compared with the corresponding analogue data. The estimated solvation entropies and enthalpies of the various amino acid side chains are compared with existing side chain analogue data. To analyze the origin of these observations, we here present a molecular simulation study on temperature dependent solvation free energies of nonpolar and polar side chains attached to a short peptide backbone. In contrast to this, the hydrophilicity of the polar side chains is hardly affected by the backbone. A recent molecular simulation study has provided evidence that all nonpolar side chains, attached to a short peptide backbone, are considerably less hydrophobic than the free side chain analogue molecules. The hydration process of side chain analogue molecules differs from that of the actual amino acid side chains in peptides and proteins owing to the effects of the peptide backbone on the aqueous solvent environment.