high-affinity endogenous ligand. The second major benefit is that one can, at least
theoretically, control the target kinase function in a more precise fashion. However, a
lot of research is needed to understand how the allosteric control mechanism works.
Currently the best molecular modeling method to tackle this question is naturally
molecular dynamics, as all other methods, like docking, QSAR, and pharmacophore,
only give a static image of the drug-receptor complex.
Allosteric effects have been explained by different theoretical frameworks, most
of which are not explained here. One of the most recent theoretical approaches is the
so-called “violin” model, specifically proposed for protein kinases by Kornev and
Taylor [56–59]. This model is developed directly to explain the type III and type IV
kinase inhibitors’ mode of action. While more traditional theories of allosteric
control rely on specific atomic interaction networks with a direct pathway from the
allosteric site to the site of action, all of them have some caveats. The most notable is
the high thermal motion of individual atoms within a protein. Unlike in the macroscopic world, thermal motion in the microcosmos is large enough to prevent simple
one-pathway networks, and big parts of the information would be lost in the process.
One can also easily understand the violin model based on the MD simulations. In the
typical force field method, atoms and bonds are represented by ball and springs with
corresponding spring constants and thus also with corresponding vibrations. These
vibrations are, even at room temperature, strong enough to constantly break and
re-make most of the interprotein interactions like H-bonds, ionic bonds, and hydrophobic (dispersion) interactions. As current force fields are accurate enough to
reproduce a majority of the macroscopic parameters and spectra data, we can easily
accept that these vibration and intramolecular motions are also represented accurately enough by modern all-atomic force fields.
Another important work dealing with allosterism, by McClendon et al. [58], is
also based on MD simulations. The work includes microsecond scale MD simulations and the authors demonstrate that Protein Kinase A (PKA) has not just semirigid N- and C-lobes, but several semi-rigid communities interacting with each other
and controlling in a rational way the function and activity of PKA. Correlated
motions between these structurally contiguous communities are associated with a
particular protein kinase function and/or a regulatory mechanism. A bit surprising is
the finding that some well-known protein kinase motifs are split into different
communities. The community maps are able to explain how different ligands induce
long-distance allosteric coupling. These communities are also in agreement with the
spine network [57].
Most of the kinase modeling studies are based on kinase domain structure alone,
but there are also MD simulations which do include the regulatory units, like SH2
and SH3. A comprehensive study, combining MD simulations, free energy calculations, in vitro functional assays, and single point mutations, suggests that the
SH2-kinase interactions are allosterically stabilizing the αC-helix of the c-Abl kinase
domain [60]. One should recognize that while MD simulations were used with an
unbiased classical all-atom AMBER-force field, the free-energy estimations were
based on a hybrid coarse-grained model. A multidisciplinary approach combining
simulations, functional assays, and mutagenesis has characterized the interdomain
Molecular Modeling of Protein Kinases: Current Status and Challenges
35
theoretically, control the target kinase function in a more precise fashion. However, a
lot of research is needed to understand how the allosteric control mechanism works.
Currently the best molecular modeling method to tackle this question is naturally
molecular dynamics, as all other methods, like docking, QSAR, and pharmacophore,
only give a static image of the drug-receptor complex.
Allosteric effects have been explained by different theoretical frameworks, most
of which are not explained here. One of the most recent theoretical approaches is the
so-called “violin” model, specifically proposed for protein kinases by Kornev and
Taylor [56–59]. This model is developed directly to explain the type III and type IV
kinase inhibitors’ mode of action. While more traditional theories of allosteric
control rely on specific atomic interaction networks with a direct pathway from the
allosteric site to the site of action, all of them have some caveats. The most notable is
the high thermal motion of individual atoms within a protein. Unlike in the macroscopic world, thermal motion in the microcosmos is large enough to prevent simple
one-pathway networks, and big parts of the information would be lost in the process.
One can also easily understand the violin model based on the MD simulations. In the
typical force field method, atoms and bonds are represented by ball and springs with
corresponding spring constants and thus also with corresponding vibrations. These
vibrations are, even at room temperature, strong enough to constantly break and
re-make most of the interprotein interactions like H-bonds, ionic bonds, and hydrophobic (dispersion) interactions. As current force fields are accurate enough to
reproduce a majority of the macroscopic parameters and spectra data, we can easily
accept that these vibration and intramolecular motions are also represented accurately enough by modern all-atomic force fields.
Another important work dealing with allosterism, by McClendon et al. [58], is
also based on MD simulations. The work includes microsecond scale MD simulations and the authors demonstrate that Protein Kinase A (PKA) has not just semirigid N- and C-lobes, but several semi-rigid communities interacting with each other
and controlling in a rational way the function and activity of PKA. Correlated
motions between these structurally contiguous communities are associated with a
particular protein kinase function and/or a regulatory mechanism. A bit surprising is
the finding that some well-known protein kinase motifs are split into different
communities. The community maps are able to explain how different ligands induce
long-distance allosteric coupling. These communities are also in agreement with the
spine network [57].
Most of the kinase modeling studies are based on kinase domain structure alone,
but there are also MD simulations which do include the regulatory units, like SH2
and SH3. A comprehensive study, combining MD simulations, free energy calculations, in vitro functional assays, and single point mutations, suggests that the
SH2-kinase interactions are allosterically stabilizing the αC-helix of the c-Abl kinase
domain [60]. One should recognize that while MD simulations were used with an
unbiased classical all-atom AMBER-force field, the free-energy estimations were
based on a hybrid coarse-grained model. A multidisciplinary approach combining
simulations, functional assays, and mutagenesis has characterized the interdomain
Molecular Modeling of Protein Kinases: Current Status and Challenges
35