title: Effect of glutamate side chain length on intrahelical glutamate-lysine ion pairing interactions.
abstract: Ion pairing interactions between oppositely charged amino acids are important for protein structure stability. Despite the apparent electrostatic nature of these interactions, the charged amino acids Lys, Arg, Glu, and Asp have a different number of hydrophobic methylenes linking the charged functionality to the backbone. To investigate the effect of Glu (and Asp) side chain length on ion pairing interactions, a series of 36 monomeric α-helical peptides containing Zbb-Xaa (i, i+3), (i, i+4), and (i, i+5) (Zbb = Aad, Glu, Asp; Xaa = Lys, Orn, Dab, Dap) sequence patterns were studied by circular dichroism (CD) spectroscopy at pH 7 and 2. Peptides with Glu and Aad exhibited similar helicity and pH dependence, whereas peptides with Asp behaved distinctly different. The side chain interaction energetics were derived from the CD data using the nesting block method coupled with modified Lifson-Roig theory. At pH 7, no Zbb-Xaa (i, i+5) interaction was observed, regardless of side chain length (consistent with the helix geometry). Interestingly, only Lys was capable of supporting Zbb-Xaa (i, i+3) interactions, whereas any Xaa side chain length supported Zbb-Xaa (i, i+4) interactions. In particular, the magnitude of both Zbb(-)-Lys (i, i+4) and Zbb(-)-Orn (i, i+4) interaction energies followed the trend Asp > Glu > Aad. Side chain conformational analysis by molecular mechanics calculations showed that the Zbb-Xaa (i, i+3) interactions involved the χ(1) dihedral combination (g+, g+) for the i and i+3 residues, whereas the Zbb-Xaa (i, i+4) interactions were supported by the χ(1) dihedral combination (t, g+) for the i and i+4 residues. These calculated low energy conformers were consistent with conformations of intrahelical Asp-Lys and Glu-Lys salt bridges in a nonredundant protein structure database. These results suggest that Asp and Glu provide natural variation, and lengthening the Glu side chain further to Aad does not furnish additional characteristics that Glu cannot supply.
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan. rpcheng@ntu.edu.tw
authors.forename: Richard P
authors.initials: RP
authors.lastname: Cheng
authors.forename: Wei-Ren
authors.initials: WR
authors.lastname: Wang
authors.forename: Prashant
authors.initials: P
authors.lastname: Girinath
authors.forename: Po-An
authors.initials: PA
authors.lastname: Yang
authors.forename: Raheel
authors.initials: R
authors.lastname: Ahmad
authors.forename: Jhe-Hao
authors.initials: JH
authors.lastname: Li
authors.forename: Pier
authors.initials: P
authors.lastname: Hart
authors.forename: Bashkim
authors.initials: B
authors.lastname: Kokona
authors.forename: Robert
authors.initials: R
authors.lastname: Fairman
authors.forename: Casey
authors.initials: C
authors.lastname: Kilpatrick
authors.forename: Annmarie
authors.initials: A
authors.lastname: Argiros
mesh_terms: D000595:Amino Acid Sequence; D030562:Databases, Protein; D015195:Drug Design; D018698:Glutamic Acid / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008239:Lysine / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D009842:Oligopeptides; D018698:Glutamic Acid; D008239:Lysine