| Abstrakt: |
Our aim was to use molecular modeling to determine the solution conformations of small peptides (2–6 residues), which are substrates for both peptide transporters and peptidases, and can be clinically important as the basis of various therapeutic agents including β-lactams and ACE inhibitors. We evaluated two conformational search strategies and, in particular, the influence of electrostatic charge and dielectric constant on the results. AlaAla (uncharged), AlaAla (charged), N-acetyl-Ala-Ala- O-methyl and N-acetyl-Ala-Ala-methylamide were modeled using grid search and random search as implemented within SYBYL 6.4 using distance-dependent dielectric constants of between 1 (in vacuo) and 80 (water). The two search procedures located similar energy minima for both forms of AlaAla at any given dielectric constant, indicating that random searches sample conformational space sufficiently well for dipeptides at least. Analyses of the minimum-energy conformers computed for each molecule showed that, whereas the dielectric constant had minimal effect for AlaAla (uncharged), N-acetyl-Ala-Ala- O-methyl and N-acetyl-Ala-Ala-methylamide, for AlaAla (charged), as the dielectric constant approached 1 (in vacuo), this conformer had a cis peptide bond and was the only conformer present. We conclude that it is essential to model peptides in their charged forms at dielectric constants of approximately 80 to be able to determine the solution conformations of peptides recognized by peptidases and peptide transporters. [ABSTRACT FROM AUTHOR] |
Full text from SpringerLink