Do cooperative cycles of hydrogen bonding exist in proteins?

TL;DR

This paper investigates the existence of cooperative hydrogen bond cycles in proteins and finds no evidence for such cycles, highlighting the nature of hydrogen bonding and implications for polymer design.

Contribution

It provides a detailed analysis of hydrogen bonding in proteins, showing that cooperative HB cycles are absent and clarifying the nature of inter-amide hydrogen bonds.

Findings

No evidence of cooperative HB cycles in proteins.

Hydrogen bonds are mainly due to resonance and electrostatic effects.

Insights into amide geometry favoring hydrogen bonding.

Abstract

The closure of cooperative chains of Hydrogen Bonding, HB, to form cycles can enhance cooperativity. Cycles of charge transfer can balance charge into and out of every site, eliminating the charge build-up that limits the cooperativity of open unidirectional cooperative chains. If cycles of cooperative HB exist in proteins, these could be expected to be significant in protein structure and function in ways described below. We find no mention of an example of this kind of cycle in the literature. We investigate whether cooperative HB cycles not traversing solvent, ligand or modified residues occur in proteins by means including search of Nuclear Magnetic Resonance spectroscopy entries of the Protein Data Bank. For the direct interactions of inter-amide HB, when the energy associated with Natural Bond Orbital, NBO, steric exchange is deducted from that of NBO donor-acceptor interactions, the result is close to zero, so that HB is not primarily due to the sum of direct inter-amide NBO interactions. The NBO binding energy is primarily associated with the increase in resonance of the amides, a consequence of which is that the majority of the NBO binding energy is susceptible to variation by electrostatic field with component parallel or antiparallel to an amide C-N bond. The question of what geometry most favours HB in amides is revisited with emphasis on the inequivalence of amide/carbonyl oxygen lone pairs. A possible avenue for the design of HB-chaining polymers with improved stability is discussed.