44. Asquith CRM, Maffuid KA, Laitinen T, Torrice CD, Tizzard GJ, Crona DJ, Zuercher WJ
(2019) Targeting an EGFR water network with 4-anilinoquin(az)oline inhibitors for chordoma.
ChemMedChem 14:1693–1700. https://doi.org/10.1002/cmdc.201900428
45. Heider F, Pantsar T, Kudolo M, Ansideri F, Simone AD, Pruccoli L, Schneider T, Goettert MI,
Tarozzi A, Andrisano V, Laufer SA, Koch P (2019) Pyridinylimidazoles as GSK3β inhibitors:
the impact of tautomerism on compound activity via water networks. ACS Med Chem Lett
10:1407–1414. https://doi.org/10.1021/acsmedchemlett.9b00177
46. Khandogin J, Brooks CL (2005) Constant pH molecular dynamics with proton tautomerism.
Biophys J 89:141–157. https://doi.org/10.1529/biophysj.105.061341
47. Lee MS, Salsbury FR, Brooks CL (2004) Constant-pH molecular dynamics using continuous
titration coordinates. Proteins 56:738–752. https://doi.org/10.1002/prot.20128
48. Tsai C-C, Yue Z, Shen J (2019) How electrostatic coupling enables conformational plasticity in
a tyrosine kinase. J Am Chem Soc 141:15092–15101. https://doi.org/10.1021/jacs.9b06064
49. Liu R, Yue Z, Tsai C-C, Shen J (2019) Assessing lysine and cysteine reactivities for designing
targeted covalent kinase inhibitors. J Am Chem Soc 141:6553–6560. https://doi.org/10.1021/
jacs.8b13248
50. Kuzmanic A, Sutto L, Saladino G, Nebreda AR, Gervasio FL, Orozco M (2017) Changes in the
free-energy landscape of p38α MAP kinase through its canonical activation and binding events
as studied by enhanced molecular dynamics simulations. Elife 6:e22175. https://doi.org/10.
7554/elife.22175
51. Zhang Y-Y, Wu J-W, Wang Z-X (2011) Mitogen-activated protein kinase (MAPK) phosphatase 3-mediated cross-talk between MAPKs ERK2 and p38α. J Biol Chem 286:16150–16162.
https://doi.org/10.1074/jbc.m110.203786
52. Tokunaga Y, Takeuchi K, Takahashi H, Shimada I (2014) Allosteric enhancement of MAP
kinase p38α’s activity and substrate selectivity by docking interactions. Nat Struct Mol Biol
21:704–711. https://doi.org/10.1038/nsmb.2861
53. Lake EW, Muretta JM, Thompson AR, Rasmussen DM, Majumdar A, Faber EB, Ruff EF,
Thomas DD, Levinson NM (2018) Quantitative conformational profiling of kinase inhibitors
reveals origins of selectivity for Aurora kinase activation states. Proc Natl Acad Sci U S A 115:
E11894–E11903. https://doi.org/10.1073/pnas.1811158115
54. Ruff EF, Muretta JM, Thompson AR, Lake EW, Cyphers S, Albanese SK, Hanson SM, Behr
JM, Thomas DD, Chodera JD, Levinson NM (2018) A dynamic mechanism for allosteric
activation of Aurora kinase A by activation loop phosphorylation. Elife 7:e32766. https://doi.
org/10.7554/elife.32766
55. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural
mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289:1938–1942. https://
doi.org/10.1126/science.289.5486.1938
56. Ahuja LG, Taylor SS, Kornev AP (2019) Tuning the “violin” of protein kinases: the role of
dynamics-based allostery. IUBMB Life 71:685–696. https://doi.org/10.1002/iub.2057
57. Kornev AP, Taylor SS (2015) Dynamics-driven allostery in protein kinases. Trends Biochem
Sci 40:628–647. https://doi.org/10.1016/j.tibs.2015.09.002
58. McClendon CL, Kornev AP, Gilson MK, Taylor SS (2014) Dynamic architecture of a protein
kinase. Proc Natl Acad Sci U S A 111:E4623–E4631. https://doi.org/10.1073/pnas.1418402111
59. Kornev AP (2020) Allostery explained through synchronized oscillators and fractal networks.
Biophys J 118:208a. https://doi.org/10.1016/j.bpj.2019.11.1248
60. Dölker N, Górna MW, Sutto L, Torralba AS, Superti-Furga G, Gervasio FL (2014) The SH2
domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the
hinge motion. PLoS Comput Biol 10:e1003863. https://doi.org/10.1371/journal.pcbi.1003863
61. Tse A, Verkhivker GM (2015) Molecular dynamics simulations and structural network analysis
of c-Abl and c-Src kinase core proteins: capturing allosteric mechanisms and communication
pathways from residue centrality. J Chem Inf Model 55:1645–1662. https://doi.org/10.1021/
acs.jcim.5b00240
40
A. Poso
(2019) Targeting an EGFR water network with 4-anilinoquin(az)oline inhibitors for chordoma.
ChemMedChem 14:1693–1700. https://doi.org/10.1002/cmdc.201900428
45. Heider F, Pantsar T, Kudolo M, Ansideri F, Simone AD, Pruccoli L, Schneider T, Goettert MI,
Tarozzi A, Andrisano V, Laufer SA, Koch P (2019) Pyridinylimidazoles as GSK3β inhibitors:
the impact of tautomerism on compound activity via water networks. ACS Med Chem Lett
10:1407–1414. https://doi.org/10.1021/acsmedchemlett.9b00177
46. Khandogin J, Brooks CL (2005) Constant pH molecular dynamics with proton tautomerism.
Biophys J 89:141–157. https://doi.org/10.1529/biophysj.105.061341
47. Lee MS, Salsbury FR, Brooks CL (2004) Constant-pH molecular dynamics using continuous
titration coordinates. Proteins 56:738–752. https://doi.org/10.1002/prot.20128
48. Tsai C-C, Yue Z, Shen J (2019) How electrostatic coupling enables conformational plasticity in
a tyrosine kinase. J Am Chem Soc 141:15092–15101. https://doi.org/10.1021/jacs.9b06064
49. Liu R, Yue Z, Tsai C-C, Shen J (2019) Assessing lysine and cysteine reactivities for designing
targeted covalent kinase inhibitors. J Am Chem Soc 141:6553–6560. https://doi.org/10.1021/
jacs.8b13248
50. Kuzmanic A, Sutto L, Saladino G, Nebreda AR, Gervasio FL, Orozco M (2017) Changes in the
free-energy landscape of p38α MAP kinase through its canonical activation and binding events
as studied by enhanced molecular dynamics simulations. Elife 6:e22175. https://doi.org/10.
7554/elife.22175
51. Zhang Y-Y, Wu J-W, Wang Z-X (2011) Mitogen-activated protein kinase (MAPK) phosphatase 3-mediated cross-talk between MAPKs ERK2 and p38α. J Biol Chem 286:16150–16162.
https://doi.org/10.1074/jbc.m110.203786
52. Tokunaga Y, Takeuchi K, Takahashi H, Shimada I (2014) Allosteric enhancement of MAP
kinase p38α’s activity and substrate selectivity by docking interactions. Nat Struct Mol Biol
21:704–711. https://doi.org/10.1038/nsmb.2861
53. Lake EW, Muretta JM, Thompson AR, Rasmussen DM, Majumdar A, Faber EB, Ruff EF,
Thomas DD, Levinson NM (2018) Quantitative conformational profiling of kinase inhibitors
reveals origins of selectivity for Aurora kinase activation states. Proc Natl Acad Sci U S A 115:
E11894–E11903. https://doi.org/10.1073/pnas.1811158115
54. Ruff EF, Muretta JM, Thompson AR, Lake EW, Cyphers S, Albanese SK, Hanson SM, Behr
JM, Thomas DD, Chodera JD, Levinson NM (2018) A dynamic mechanism for allosteric
activation of Aurora kinase A by activation loop phosphorylation. Elife 7:e32766. https://doi.
org/10.7554/elife.32766
55. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural
mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289:1938–1942. https://
doi.org/10.1126/science.289.5486.1938
56. Ahuja LG, Taylor SS, Kornev AP (2019) Tuning the “violin” of protein kinases: the role of
dynamics-based allostery. IUBMB Life 71:685–696. https://doi.org/10.1002/iub.2057
57. Kornev AP, Taylor SS (2015) Dynamics-driven allostery in protein kinases. Trends Biochem
Sci 40:628–647. https://doi.org/10.1016/j.tibs.2015.09.002
58. McClendon CL, Kornev AP, Gilson MK, Taylor SS (2014) Dynamic architecture of a protein
kinase. Proc Natl Acad Sci U S A 111:E4623–E4631. https://doi.org/10.1073/pnas.1418402111
59. Kornev AP (2020) Allostery explained through synchronized oscillators and fractal networks.
Biophys J 118:208a. https://doi.org/10.1016/j.bpj.2019.11.1248
60. Dölker N, Górna MW, Sutto L, Torralba AS, Superti-Furga G, Gervasio FL (2014) The SH2
domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the
hinge motion. PLoS Comput Biol 10:e1003863. https://doi.org/10.1371/journal.pcbi.1003863
61. Tse A, Verkhivker GM (2015) Molecular dynamics simulations and structural network analysis
of c-Abl and c-Src kinase core proteins: capturing allosteric mechanisms and communication
pathways from residue centrality. J Chem Inf Model 55:1645–1662. https://doi.org/10.1021/
acs.jcim.5b00240
40
A. Poso