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reactivity surface of molecular sites. Protonation and/or deprotonation are
the first step in many fundamental molecular rearrangements and in most
of the enzymatic reactions [11]. Some ions and molecules can undergo
protonation in more than one sites, and these are labeled as polybasics,
which represent many biological macromolecules. In protein and RNA
macromolecules, only a limited number of different side-chain chemical
groups are available to function as catalysts. The myriad of enzyme-cata-
lyzed reactions results from the ability of most of these groups to function
either as nucleophilic, electrophilic, or general acid-base catalysts. And
the key to their adapted chemical function lies in their states of protonation
[12]. Protonation is also an essential step in certain analytical procedures
such as electrospray mass spectrometry. The proton transfer (PT) reactions
are of great importance in chemistry and in biomolecular processes of liv-
ing organisms. The latter includes most enzymatically catalyzed reactions
such as ATP hydrolysis/synthesis. Further, the protonation state of chemi-
cal groups, for example, the side chains of amino acids, is fundamentally
related to their biomolecular function [5, 11, 13-15].
Shan et al. [16] demonstrated the importance of conformation change
in many protein kinases. Many kinase inhibitors—including the cancer
drug imatinib—selectively target a specifi c DFG conformation, but the
function and mechanism of the fl ip remain unclear. Using long molecular
dynamics simulations of the Abl kinase, Yibing et al. visualized the DFG
fl ip in atomic-level detail and formulated an energetic model predicting
that protonation of the DFG aspartate controls the fl ip. Shan et al. [16]
also established experimentally that the kinetics of imatinib binding to Abl
kinase have a pH dependence that disappears when the DFG aspartate is
mutated.
Protonation reaction is also important in the study of the titration be-
havior of carbonmonoxy-myoglobin (MbCO) in the pH range from 3 to 7
by conventional electrostatic continuum methods with subsequent Monte
Carlo (MC) sampling [17].
The knowledge of the intrinsic basicity and the site of protonation of
a compound in the gas phase are central to the understanding of its reac-
tivity and mechanism of chemical reactions involving proton. In recent
years, acid-base interactions are extensively studied so that experimental
techniques could be devised to permit the quantitative study of the thermo-
chemistry of the PT reaction in the gas phase [18].
 
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