Do all backbone polar groups in proteins form hydrogen bonds?

Abstract

Evidence from proteins and peptides supports the conclusion that intrapeptide hydrogen bonds stabilize the folded form of proteins. Paradoxically, evidence from small molecules supports the opposite conclusion, that intrapeptide hydrogen bonds are less favorable than peptide-water hydrogen bonds. A related issue-often lost in this debate about comparing peptide-peptide to peptide- water hydrogen bonds-involves the energetic cost of an unsatisfied hydrogen bond. Here, experiment and theory agree that breaking a hydrogen bond costs between 5 and 6 kcal/mol. Accordingly, the likelihood of finding an unsatisfied hydrogen bond in a protein is insignificant. This realization establishes a powerful rule for evaluating protein conformations.

Figure 1.

Unsatisfied main chain hydrogen bonds during molecular dynamics simulations. Data are shown for molecular dynamics simulations of the 82 residue syntenin PDZ2 domain (1r6j) (162 main chain donors and acceptors and two PRO residues). The X-ray crystal structure of this protein (Kang et al. 2004) has one internal main chain unsatisfied hydrogen bond donor, LEU233 N.