Graham Worth and Rebecca Wade*

European Molecular Biology Laboratory, Meyerhofstr. 1,69012 Heidelberg, Germany.

The tetrapeptide, YTGP, corresponding to residues 10-13 of bovine pancreatic peptide inhibitor (BPTI), was observed by Kemmink et al. (1993) using 1H-nuclear magnetic resonance to have a non-random conformation in solution. In particular, the glycine amide hydrogen has a very anomalous chemical shift due to the ring-current effect of the tyrosine aromatic ring. The amide-aromatic interaction is also present when tyrosine is mutated to phenylalanine, but is abolished when glycine is mutated to alanine. In order to identify the contributions to the aromatic-amide interaction and the reasons for its observed sequence dependence, molecular dynamics simulations of YTGP, FTGP and YTAP were carried out.
The simulations were performed using the CHARMM22 all-atom force-field, both with and without explicit solvent molecules. Chemical shifts were calculated using the MULTISHIFT program (Williamson,M.P. and Asakura,T. (1993)). The simulations show that although the conformers observed can be described by the relative orientations of the amide group to the aromatic ring, this interaction is not the driving force for folding. Instead, the conformations adopted by each peptide are guided by a balance between energetic and entropic contributions from the whole system, including the solvent. Conformers generated in simulations without explicit solvent molecules do not correspond to those observed experimentally in aqueous solution, showing that the packing and hydrogen-bonding capabilities of the surrounding water molecules are essential. In simulations with apolar solvent molecules, the intra-molecular energy is the dominating factor, whereas in polar solvent, the solute-solvent interaction and solvent entropy become important factors in determining peptide conformation.

AIP Conference Proceedings (1995) 330, 410.

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