Pegylation Increases The Strength Of A Nearby Nh-Pi Hydrogen Bond In The Ww Domain

Here we show that an NH-pi interaction between a highly conserved Asnand a nearby Trp stabilizes the WW domain of the human protein Pinl. The strength of this NH-pi interaction depends on the structure of the arene, with NH-pi interactions involving Trp or naphthylalanine being substantially more stabilizing than those involving Tyr or Phe. Calculations suggest arene size and polarizability are key structural determinants of NH-pi-interaction strength. Methylation or PEGylation of the Asn side-chain amide nitrogen each strengthens the associated NH-pi interaction, though likely for different reasons. We hypothesize that rnethylation introduces steric clashes that destabilize conformations in which the NH-pi interaction is not possible, whereas PEGylation strengthens the NH-pi interaction via localized desolvation of the protein surface.