Effect of charged amino acid side chain length on lateral cross-strand interactions between carboxylate- and guanidinium-containing residues in a β-hairpin

Abstract

β-Sheet is one of the major protein secondary structures. Oppositely charged residues are frequently observed across neighboring strands in antiparallel sheets, suggesting the importance of cross-strand ion pairing interactions. The charged amino acids Asp, Glu, Arg, and Lys have different numbers of hydrophobic methylenes linking the charged functionality to the backbone. To investigate the effect of side chain length of guanidinium- and carboxylate-containing residues on lateral cross-strand ion pairing interactions at non-hydrogen-bonded positions, β-hairpin peptides containing Zbb-Agx (Zbb = Asp, Glu, Aad in increasing length; Agx = Agh, Arg, Agb, Agp in decreasing length) sequence patterns were studied by NMR methods. The fraction folded population and folding energy were derived from the chemical shift deviation data. Peptides with high fraction folded populations involved charged residue side chain lengths that supported high strand propensity. Double mutant cycle analysis was used to determine the interaction energy for the potential lateral ion pairs. Minimal interaction was observed between residues with short side chains, most likely due to the diffused positive charge on the guanidinium group, which weakened cross-strand electrostatic interactions with the carboxylate side chain. Only the Aad-Arg/Agh interactions with long side chains clearly exhibited stabilizing energetics, possibly relying on hydrophobics. A survey of a non-redundant protein structure database revealed that the statistical sheet pair propensity followed the trend Asp-Arg < Glu-Arg, implying the need for matching long side chains. This suggested the need for long side chains on both guanidinium-bearing and carboxylate-bearing residues to stabilize the β-hairpin motif.

Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils

“…We thus constructed various models hierarchically in order to investigate the effect of a salt-bridge formed by Glu and Lys on the stability of the αS fibril models (Table 1). The effect of charged residues on the stability of the β-strand has been well recognized [53, 54], thus worth examining in the context of αS fibrils.…”

Domain Mapping of Heat Shock Protein 70 Reveals That Glutamic Acid 446 and Arginine 447 Are Critical for Regulating Superoxide Dismutase 2 Function

“…the stability of the ␤ sheet sandwich that might affect the affinity of SOD2/hsp70 interactions and, thus, SOD2 function (20,21). Substituting alanine for glutamic acid (E446A) and arginine (R447A) attenuated the ability of the GERAMT peptide to reduce SOD2 activity more than other substitutions (Fig.…”

“…Therefore, the interaction between hsp70 and SOD2 likely requires proper alignment between the chaperone and antioxidant. Further, structural features of SOD2 also facilitate binding to hsp70, and these may include a region of hydrophobicity in the N-terminal domain, intermolecular hydrogen bonds, and van der Waal interactions between adjacent residues in SOD2 and hsp70 (20,21).…”

Design and structural characterisation of monomeric water-soluble α-helix and β-hairpin peptides: State-of-the-art

“…In contrast to α-helices, N-terminal acetylation and Cterminal amidation decreases β-hairpin stability [209]. Recently, the effects of Asp/Arg and Glu/Arg pairs, as well as for pairs containing Glu and Arg analogues with different lengths of the aliphatic chain, have been examined at nonHB sites [228]. As detailed in section 6, these contributions are pH-dependent.…”