Interplay of Hydrogen Bonds and n→π* Interactions in Proteins

Abstract

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→π* 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→π* 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→π* interaction. Then, we employed Natural Bond Orbital analysis to determine the relative energetic contributions of the hydrogen bonds and n→π* interactions in these systems. We find that an n→π* interaction is worth ~5–25% of a hydrogen bond and that stronger hydrogen bonds tend to attenuate or obscure n→π* interactions. Conversely, weaker hydrogen bonds correlate with stronger n→π* interactions and the 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→π* interactions in the inventory of non-covalent forces that contribute to protein stability and, thus, forcefields for biomolecular modeling.

Conformational flexibility of PPII-helix: A density functional theory study

“…Recently, extensive studies suggested a kind of long-range non-covalent interaction caused by electron delocalization named n → * interaction might be important for protein folding [14][15][16][17][18][19]. This interaction happens between carbonyls of peptides that the lone electrons of donor oxygen atom are delocalized over the antibonding orbital (*) of another carbonyl [16,20].…”

On the satisfaction of backbone‐carbonyl lone pairs of electrons in protein structures

“…The first lone pair participates in the NH i !C@O i-4 hydrogen bond, or n!r* interaction, leaving the second lone pair available to make an n!p* interaction with the adjacent carbonyl group. 16 Our analysis also revealed that half of carbonyl groups found in b-structure not satisfied by hydrogen bonds to water were satisfied by one backbone NH hydrogen bond (NH bb ), plus one C a -H hydrogen bond (CaH), (55%), Figure 3(A). Both of these bridge strands [ Fig.…”

“…Interestingly, when these interactions did fluctuate down to two NCI C@O in the MD simulations, it was usually one of the NH bb that was lost, and not the n!p* interaction, which perhaps runs contrary to expectations given that the latter is considered the weaker of the two interactions. 16 A third type of three-NCI C@O cluster was found in the C-terminal turns of a-helices [31 unique examples from 1039 snapshots, Fig. 4(C)].…”

“…[5][6][7][8][9] More specifically, other hydrogen-bond-like, NCIs have been implicated, including the n!p* interaction [10][11][12] and methyl-p interactions. 13,14 These particular interactions are much weaker than canonical hydrogen bonds: the latter are typically worth 3-10 kcal/ mol 15,16 ; whereas, n!p* interactions are estimated at 0.7-1.2 kcal/mol, 10,16 and methyl-p interactions at 0.9-1.5 kcal/mol. 17,18 These share common features with hydrogen bonds; notably, the overlap of van der Waals' radii and orbital overlap, which result in structure stabilization through electron delocalization.…”

“…17,18 These share common features with hydrogen bonds; notably, the overlap of van der Waals' radii and orbital overlap, which result in structure stabilization through electron delocalization. Recently, we demonstrated an interplay between hydrogen bonds and n!p* interactions, 16 in particular with asparagine and aspartic acid residues, which form both hydrogen bonds and n!p* interactions via their side chain carbonyl groups.…”