Interplay of Hydrogen Bonds and n ->pi* Interactions in Proteins

Gail J. Bartlett, Robert W. Newberry, Brett VanVeller, Ronald T. Raines*, Derek N. Woolfson

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

110 Citations (Scopus)


Protein structures are stabilized by multiple weak interactions, including the hydrophobic effect, hydrogen bonds, electrostatic effects, and van der Waals interactions. Among these interactions, the hydrogen bond is distinct in having its origins in electron delocalization. Recently, another type of electron delocalization, the n ->pi* interaction between carbonyl groups, has been shown to play a role in stabilizing protein structure. Here we examine the interplay between hydrogen bonding and n ->pi* interactions. To address this issue, we used data available from high-resolution protein crystal structures to interrogate asparagine side-chain oxygen atoms that are both acceptors of a hydrogen bond and donors of an n ->pi* interaction. Then we employed natural bond orbital analysis to determine the relative energetic contributions of the hydrogen bonds and n ->pi* interactions in these systems. We found that an n ->pi* interaction is worth similar to 5-25% of a hydrogen bond and that stronger hydrogen bonds tend to attenuate or obscure n ->pi* interactions. Conversely, weaker hydrogen bonds correlate with stronger n ->pi* interactions and demixing of the orbitals occupied by the oxygen lone pairs. Thus, these two interactions conspire to stabilize local backbone side-chain contacts, which argues for the inclusion of n ->pi* interactions in the inventory of non-covalent forces that contribute to protein stability and thus in force fields for biomolecular modeling.

Original languageEnglish
Pages (from-to)18682-18688
Number of pages7
JournalJournal of the American Chemical Society
Issue number49
Publication statusPublished - 11 Dec 2013




Dive into the research topics of 'Interplay of Hydrogen Bonds and n ->pi* Interactions in Proteins'. Together they form a unique fingerprint.

Cite this