Abstract
The delicate balance of noncovalent interactions determines the three dimensional structure of peptides and proteins. These interactions include hydrogen bonds, salt bridges, weakly polar interactions and the hydrophobic effect. Weakly polar interaction can be between aromatic side chains of amino acids and amides of the polypeptide backbone (Ar-HN). Although, it is known that Ar-HN interactions can be responsible for the formation of local structures in polypeptides, the detailed understanding of their role and significance in peptide and protein structure remains unclear.|In the present study Ar-HN interactions in model peptides and proteins are investigated. Protein database survey of Ar-HN interactions found that Ar(i)-HN(i+l, i+2 and i+3) interactions are more common (7.10%, 2.08% and 0.54%, respectively) than are Ar(i)-HN(i-l, i-2 and i-3) interactions (0.66%, <0.1% and 0.18%, respectively). Ar- HN interactions constrain the x' torsion angle of the aromatic residue. Analyses of the secondary structures of the protein fragments containing Ar-HN interactions showed that Ar-HN interactions were in all types of secondary structures. Search results suggest that Ar-HN interactions have a stabilizing effect on all types of secondary structures.|Interactions between the side chain aromatic rings and hydrogens of backbone amides and CHn of aliphatic groups (tt-CH) were found to constrain individual conformations of the Pro-Xaa (where Xaa is either Phe, Tyr or Trp) and Xaa-Pro fragments. These local structures were found to be independent of the secondary structure of the polypeptide chains in which the fragments were located. This suggests,that weakly polar interactions, like Ar-HN and rr-CH, are weak separately, but in combination, they can have significant influence on the stability of polypeptide structure.|The interaction between the aromatic side chain of the z'th residue and the backbone amide group of the i+2 residue was studied in the tripeptide acetyl-Phe-Gly- Gly-N-methyl amide. It is an ideal model peptide to study such interactions, since side chains in positions i+1 and i+2 do not interfere with the formation of Ar-HN interaction. Simulated annealing studies with and without implicit solvation model using three different force fields (Amber 5.0, CHARMM22 and OPLSAA) found that lowest energy structures of the model peptide contained Ar-HN interaction. Molecular dynamics (MD) simulations revealed, that Ar(i)-HN(i+l) interactions were four times more frequent than were Ar(i)-HN(i+2) interactions in acetyl-Phe-Gly-Gly-N-methyl amide, and that half of the conformations with Ar(i)-HN(i+2) interactions also contained an Ar(i)-HN(i+l) interaction. The solvent access surface area of the Phel side-chain and of the amide groups of Phel, Gly2 and Gly3 involved in Ar-HN interactions was significantly smaller than in residues not involved in such interactions. The number of hydrogen bonds between the solvent and Phel, Gly2 and Gly3 amide groups was also lower in conformations with Ar-HN interactions. Thus, the attractive force between the backbone amide and the side chain aromatic ring is strong enough to outweigh any free energy losses due to solvation of the backbone and entropic costs of backbone and side chain stabilization.|The interaction between the aromatic side chain of Tyr and the a-helical backbone was investigated by studying a-helix stability in Ala based model peptides, with Tyr replacement in the N-terminal and inner helical positions, using circular dichroism, ’H-NMR and molecular dynamics simulations (MD). Interaction between the aromatic ring and the backbone highly depended on the orientation of the aromatic ring to the helical backbone since aromatic-backbone amide, -carbonyl and -aCH interactions were observed in MD. Solvent screening by the aromatic side chain decreased the solvent accessible surface area of some polar backbone groups by more than 80%. The fractional helical content, determined by NMR, suggested that Tyr in inner helical positions destabilized the helix in the peptides, while in N-terminal positions Tyr had the same helix stabilizing effect as had Ala.