Evaluation of C-H•••O hydrogen bonds in native and misfolded proteins

Non-traditional C-H...Y hydrogen bonds, in which a carbon atom acts as the hydrogen donor and an electronegative atom Y (Y = N, O or S) acts as the acceptor, have been reported in proteins, but their importance in protein structures is not well established. Here, we present the results of three computational tests that examine the significance of C-H... Y bonds involving the C-alpha in proteins. First, we compared the number of C-alpha-H...Y bonds in native structures with two sets of compact, energy-minimized decoy structures. The decoy structures contain about as many C-alpha-H...Y bonds as the native structures, indicating that the constraints of chain connectivity and compactness can lead to incidental formation of C-alpha-H...Y bonds. Secondly, we examined whether short C-H... Y bonds have a tendency to be linear, as is expected for a cohesive hydrogen-bonding interaction. The native structures do show this trend, but so does one of the decoy sets, suggesting that this criterion is also not sufficient to indicate a stabilizing interaction. Finally, we examined the preference for C-alpha-H...Y bond donors to be near to strong hydrogen bond acceptors. In the native proteins, the alpha protons attract strong acceptors like oxygen atoms more than weak acceptors. In contrast, hydrogen bond donors in the decoy structures do not distinguish between strong and weak acceptors. Thus, any individual C-alpha-H...Y bond may be fortuitous and occur due to the polypeptide connectivity and compactness. Taken collectively, however, C-alpha-H...Y bonds provide a weakly cohesive force that stabilizes proteins. (C) 2002 Elsevier Science Ltd. All rights reserved.