uses, improvements, and extensions of the methodologies
described in this chapter that solidify the RTA analysis and further
validation with experimental data. A remarkable strength of the
RTA procedure is that we can detect and attain information about
complex allosteric communication using only a single 3D snapshot
(coordinates) without doing long, complex, and expensive simulations. Due to the speed of the underlying algorithms, RTA procedure is well suited for high throughput allostery analysis. This
should eventually allow us to obtain a better understanding of
allostery and functionally important features in protein signaling
and ultimately have tools to tackle complicated signaling events in
the cell.
References
1. Fenton AW (2008) Allostery: an illustrated
definition for the “second secret of life”.
Trends Biochem Sci 33:420–425
2. Nussinov R, Tsai CJ (2013) Allostery in disease
and drug discovery. Cell 153(2):293–305
3. Liu J, Nussinov R (2016) Allostery: an overview of its history, concepts, methods, and
applications. PLoS Comput Biol 12(6):
e1004966
4. Gunasekaran K, Ma M, Nussinov R (2004) Is
allostery an intrinsic property of all dynamic
proteins? Proteins 57:433443
5. Changeux JP, Jacob F, Monod J (1963) Allosteric proteins and cellular control systems. J
Mol Biol 6:306–329
6. Whiteley W (1996) Some Matroids from discrete applied geometry. In: Bonin J, Oxley J,
Servatius B (eds) Matroid theory, volume
197 of Contemp. Math. American Mathematical Society, Providence, pp 171–311
7. Whiteley W (2005) Counting out to the fexibility of molecules. Phys Biol 2:S116–S126
8. Sljoka A (2012) Algorithms in rigidity theory
with applications to protein flexibility and
mechanical linkages. PhD thesis, York University, Toronto
9. Finbow-Singh W, Whiteley W (2013) Isostatic
block and hole frameworks. Siam J Discr Math
27:991–1020
10. Kim TH, Mehrabi P, Ren A, Sljoka A, Ing C,
Bezginov A, Ye LB, Pomes R, Prosser RS, Pai
EF (2017) The role of dimer asymmetry and
protomer dynamics in enzyme catalysis. Science 355:262–U287
11. Ye L, Neale C, Sljoka A, Pichugin D,
Tsuchimura N, Sunahara R, Prosser S et al
(2018) Bidirectional regulation of the A2A
adenosine G protein-coupled receptor by physiological cations. Nat Commun 9:1372
12. Deng B, Zhu S, Macklin AM, Xu J, Lento C,
Sljoka A, Wilson D (2017) Suppressing allostery in epitope mapping experiments using
millisecond hydrogen/deuterium exchange
mass spectrometry. MAbs 1:10
13. Kuhn LA, Rader DJ, Thorpe MF (2001) Protein exibility predictions using graph theory.
Proteins 44:150–165
14. Wildman H, Kern KD (2007) Dynamic personalities of proteins. Nature 450:964–972
15. Lewandowski JR, Halse ME, Blackledge M,
Emsley L (2015) Direct observation of hierarchical protein dynamics. Science 348
(6234):578–581
16. Sljoka A, Wilson D (2013) Probing protein
ensemble rigidity and predictions of
hydrogen-deuterium exchange. Phys Biol
10:056013
17. Hartl FU, Hayer-Hartl M (2009) Converging
concepts of protein folding in vitro and in vivo.
Nat Struct Mol Biol 16:574–581
18. Shaw DE et al (2008) Anton, a special-purpose
machine for molecular dynamics. Commun
ACM 51(7):9197
19. Katoh N, Tanigawa S (2011) A proof of the
molecular conjecture. Discrete Comput Geom
45:647–700
20. Schulze B, Sljoka A, Whiteley W (2014) How
does symmetry impact the flexibility of proteins? Philos Transact Royal Soc A
372:20120041
21. Jeliazkov JR, Sljoka A, Kuroda D,
Tsuchimura N, Katoh N, Tsumoto K, Gray JJ
(2018) Repertoire analysis of antibody
CDR-H3 loops suggests affinity maturation
does not typically result in rigidification.
Front Immunol 9:413
22. Hermans SMA et al (2017) Rigidity theory for
biomolecules:
concepts,
software,
and
74
Adnan Sljoka
described in this chapter that solidify the RTA analysis and further
validation with experimental data. A remarkable strength of the
RTA procedure is that we can detect and attain information about
complex allosteric communication using only a single 3D snapshot
(coordinates) without doing long, complex, and expensive simulations. Due to the speed of the underlying algorithms, RTA procedure is well suited for high throughput allostery analysis. This
should eventually allow us to obtain a better understanding of
allostery and functionally important features in protein signaling
and ultimately have tools to tackle complicated signaling events in
the cell.
References
1. Fenton AW (2008) Allostery: an illustrated
definition for the “second secret of life”.
Trends Biochem Sci 33:420–425
2. Nussinov R, Tsai CJ (2013) Allostery in disease
and drug discovery. Cell 153(2):293–305
3. Liu J, Nussinov R (2016) Allostery: an overview of its history, concepts, methods, and
applications. PLoS Comput Biol 12(6):
e1004966
4. Gunasekaran K, Ma M, Nussinov R (2004) Is
allostery an intrinsic property of all dynamic
proteins? Proteins 57:433443
5. Changeux JP, Jacob F, Monod J (1963) Allosteric proteins and cellular control systems. J
Mol Biol 6:306–329
6. Whiteley W (1996) Some Matroids from discrete applied geometry. In: Bonin J, Oxley J,
Servatius B (eds) Matroid theory, volume
197 of Contemp. Math. American Mathematical Society, Providence, pp 171–311
7. Whiteley W (2005) Counting out to the fexibility of molecules. Phys Biol 2:S116–S126
8. Sljoka A (2012) Algorithms in rigidity theory
with applications to protein flexibility and
mechanical linkages. PhD thesis, York University, Toronto
9. Finbow-Singh W, Whiteley W (2013) Isostatic
block and hole frameworks. Siam J Discr Math
27:991–1020
10. Kim TH, Mehrabi P, Ren A, Sljoka A, Ing C,
Bezginov A, Ye LB, Pomes R, Prosser RS, Pai
EF (2017) The role of dimer asymmetry and
protomer dynamics in enzyme catalysis. Science 355:262–U287
11. Ye L, Neale C, Sljoka A, Pichugin D,
Tsuchimura N, Sunahara R, Prosser S et al
(2018) Bidirectional regulation of the A2A
adenosine G protein-coupled receptor by physiological cations. Nat Commun 9:1372
12. Deng B, Zhu S, Macklin AM, Xu J, Lento C,
Sljoka A, Wilson D (2017) Suppressing allostery in epitope mapping experiments using
millisecond hydrogen/deuterium exchange
mass spectrometry. MAbs 1:10
13. Kuhn LA, Rader DJ, Thorpe MF (2001) Protein exibility predictions using graph theory.
Proteins 44:150–165
14. Wildman H, Kern KD (2007) Dynamic personalities of proteins. Nature 450:964–972
15. Lewandowski JR, Halse ME, Blackledge M,
Emsley L (2015) Direct observation of hierarchical protein dynamics. Science 348
(6234):578–581
16. Sljoka A, Wilson D (2013) Probing protein
ensemble rigidity and predictions of
hydrogen-deuterium exchange. Phys Biol
10:056013
17. Hartl FU, Hayer-Hartl M (2009) Converging
concepts of protein folding in vitro and in vivo.
Nat Struct Mol Biol 16:574–581
18. Shaw DE et al (2008) Anton, a special-purpose
machine for molecular dynamics. Commun
ACM 51(7):9197
19. Katoh N, Tanigawa S (2011) A proof of the
molecular conjecture. Discrete Comput Geom
45:647–700
20. Schulze B, Sljoka A, Whiteley W (2014) How
does symmetry impact the flexibility of proteins? Philos Transact Royal Soc A
372:20120041
21. Jeliazkov JR, Sljoka A, Kuroda D,
Tsuchimura N, Katoh N, Tsumoto K, Gray JJ
(2018) Repertoire analysis of antibody
CDR-H3 loops suggests affinity maturation
does not typically result in rigidification.
Front Immunol 9:413
22. Hermans SMA et al (2017) Rigidity theory for
biomolecules:
concepts,
software,
and
74
Adnan Sljoka