Proton transfer reactions and hydrogen-bond networks in protein environments

Abstract

In protein environments, proton transfer reactions occur along polar or charged residues and isolated water molecules. These species consist of H-bond networks that serve as proton transfer pathways; therefore, thorough understanding of H-bond energetics is essential when investigating proton transfer reactions in protein environments. When the pK a values (or proton affinity) of the H-bond donor and acceptor moieties are equal, significantly short, symmetric H-bonds can be formed between the two, and proton transfer reactions can occur in an efficient manner. However, such short, symmetric H-bonds are not necessarily stable when they are situated near the protein bulk surface, because the condition of matching pK a values is opposite to that required for the formation of strong salt bridges, which play a key role in protein-protein interactions. To satisfy the pK a matching condition and allow for proton transfer reactions, proteins often adjust the pK a via electron transfer reactions or H-bond pattern changes. In particular, when a symmetric H-bond is formed near the protein bulk surface as a result of one of these phenomena, its instability often results in breakage, leading to large changes in protein conformation.

Accurate ab initio calculations of O–H⋯O and O–H⋯−O proton chemical shifts: towards elucidation of the nature of the hydrogen bond and prediction of hydrogen bond distances

“…10 They are shorter (2.5 to 2.7 Å) and stronger (<−7 kcal mol −1 ) than normal hydrogen bonds and are predicted to enhance catalytic rates by more than 10 4 -fold. However, in specific cases, short and strong hydrogen bonds or lower-barrier hydrogen bonds have been proposed to contribute significantly to the catalytic power of some enzymes by stabilizing the transition state or some labile intermediate.…”

“…Fig. See DOI: 10.1039/c5ob00920k gen bond is inferred by several NMR parameters and methods such as: Plot of calculated Wiberg bond order of the C2vO1 group of the intramolecular CO⋯H(O) hydrogen bond.…”

AKT as Locus of Hydrogen Bond Network in Cancer

“…Targeting hydrogen bond as a specific element in signaling could be achieved by the hydrogen balance change which will cause complete failure of cancer robustness and complexity. Network of the complex signaling pathways for cancer cell proliferation through the Rb/AKT/NO pathway [Radisavljevic, 2004b] and the PI3 K/AKT/mTOR/ RAN pathway [Radisavljevic and Gonzalez-Flecha, 2004], cell migration through the VEGF/AKT/ICAM1 pathway [Radisavljevic et al, 2000] are achieved by the hydrogen bonds at active sites [Ishikita and Saito, 2013;Liu et al, 2015] of the AKT locus [Radisavljevic et al, 2000;Radisavljevic, 2004a Radisavljevic, ,b, 2008Radisavljevic, , 2013a Radisavljevic, ,b,c, 2015a Radisavljevic, ,b, 2016Radisavljevic and Gonzalez-Flecha, 2004]. …”

The Existence of an Isolated Hydronium Ion in the Interior of Proteins

“…In H‐bonds, a proton is more likely to populate the moiety with the higher p K a value between the two moieties (Supporting Information, Figure S2) 9c. The energy difference between the H‐bond donor and acceptor moieties corresponds to the p K a difference (Supporting Information, Figure S3).…”