Allostery is a constitutive, albeit often elusive, feature of biomolecular systems, which heavily determines their functioning. Its mechanical, entropic, long-range, ligand, and environment-dependent nature creates far from trivial interplays between residues and, in general, the secondary structure of proteins. This intricate scenario is mirrored in computational terms as different notions of “correlation” among residues and pockets can lead to different conclusions and outcomes. In this article, we put on a common ground and challenge three computational approaches for the correlation estimation task and apply them to three diverse targets of pharmaceutical interest: the androgen A2A receptor, the androgen receptor, and the EGFR kinase domain. Results show that partial results consensus can be attained, yet different notions lead to pointing the attention to different pockets and communications.
REFERENCES
1.
P. R.
Arantes
, A. C.
Patel
, and G.
Palermo
, “Emerging methods and applications to decrypt allostery in proteins and nucleic acids
,” J. Mol. Biol.
434
, 167518
(2022
).2.
L. G.
Ahuja
, S. S.
Taylor
, and A. P.
Kornev
, “Tuning the ‘violin’ of protein kinases: The role of dynamics‐based allostery
,” IUBMB Life
71
(6
), 685
–696
(2019
).3.
J.
Guo
and H.-X.
Zhou
, “Protein allostery and conformational dynamics
,” Chem. Rev.
116
(11
), 6503
–6515
(2016
).4.
A. P.
Kornev
and S. S.
Taylor
, “Dynamics-driven allostery in protein kinases
,” Trends Biochem. Sci.
40
(11
), 628
–647
(2015
).5.
J.
Liu
and R.
Nussinov
, “Allostery: An overview of its history, concepts, methods, and applications
,” PLoS Comput. Biol.
12
(6
), e1004966
(2016
).6.
S. J.
Wodak
, E.
Paci
, N. V.
Dokholyan
, I. N.
Berezovsky
, A.
Horovitz
, J.
Li
, V. J.
Hilser
, I.
Bahar
, J.
Karanicolas
, and G.
Stock
, “Allostery in its many disguises: From theory to applications
,” Structure
27
(4
), 566
–578
(2019
).7.
K. W.
East
, E.
Skeens
, J. Y.
Cui
, H. B.
Belato
, B.
Mitchell
, R.
Hsu
, V. S.
Batista
, G.
Palermo
, and G. P.
Lisi
, “NMR and computational methods for molecular resolution of allosteric pathways in enzyme complexes
,” Biophys. Rev.
12
(1
), 155
–174
(2020
).8.
R. E.
Amaro
, “Toward understanding ‘the ways’ of allosteric drugs
,” ACS Cent. Sci.
3
(9
), 925
–926
(2017
).9.
R.
Nussinov
and C.-J.
Tsai
, “Allostery in disease and in drug discovery
,” Cell
153
(2
), 293
–305
(2013
).10.
A.
Triveri
, C.
Sanchez-Martin
, L.
Torielli
, S. A.
Serapian
, F.
Marchetti
, G.
D’Acerno
, V.
Pirota
, M.
Castelli
, E.
Moroni
, M.
Ferraro
, P.
Quadrelli
, A.
Rasola
, and G.
Colombo
, “Protein allostery and ligand design: Computational design meets experiments to discover novel chemical probes
,” J. Mol. Biol.
434
, 167468
(2022
).11.
S.
Gianni
and P.
Jemth
, “Allostery frustrates the experimentalist
,” J. Mol. Biol.
435
, 167934
(2022
).12.
S.
Bowerman
and J.
Wereszczynski
, “Detecting allosteric networks using molecular dynamics simulation
,” Methods Enzymol.
578
, 429
–447
(2016
).13.
G.
La Sala
, S.
Decherchi
, M.
De Vivo
, and W.
Rocchia
, “Allosteric communication networks in proteins revealed through pocket crosstalk analysis
,” ACS Cent. Sci.
3
(9
), 949
–960
(2017
).14.
I.
Rivalta
, M. M.
Sultan
, N.-S.
Lee
, G. A.
Manley
, J. P.
Loria
, and V. S.
Batista
, “Allosteric pathways in imidazole glycerol phosphate synthase
,” Proc. Natl. Acad. Sci. U. S. A.
109
(22
), E1428
–E1436
(2012
).15.
G.
Morra
, G.
Verkhivker
, and G.
Colombo
, “Modeling signal propagation mechanisms and ligand-based conformational dynamics of the Hsp90 molecular chaperone full-length dimer
,” PLoS Comput. Biol.
5
(3
), e1000323
(2009
).16.
A.
Cooper
and D. T. F.
Dryden
, “Allostery without conformational change
,” Eur. Biophys. J.
11
(2
), 103
–109
(1984
).17.
C.
Chennubhotla
and I.
Bahar
, “Signal propagation in proteins and relation to equilibrium fluctuations
,” PLoS Comput. Biol.
3
(9
), e172
(2007
).18.
A.
Chatzigoulas
and Z.
Cournia
, “Rational design of allosteric modulators: Challenges and successes
,” Wiley Interdiscip. Rev.: Comput. Mol. Sci.
11
(6
), e1529
(2021
).19.
K.
Gunasekaran
, B.
Ma
, and R.
Nussinov
, “Is allostery an intrinsic property of all dynamic proteins?
,” Proteins: Struct., Funct., Bioinf.
57
(3
), 433
–443
(2004
).20.
Y.
Zhang
, P.
Doruker
, B.
Kaynak
, S.
Zhang
, J.
Krieger
, H.
Li
, and I.
Bahar
, “Intrinsic dynamics is evolutionarily optimized to enable allosteric behavior
,” Curr. Opin. Struct. Biol.
62
, 14
–21
(2020
).21.
A.
Ohta
, E.
Gorelik
, S. J.
Prasad
, F.
Ronchese
, D.
Lukashev
, M. K. K.
Wong
, X.
Huang
, S.
Caldwell
, K.
Liu
, and P.
Smith
, “A2A adenosine receptor protects tumors from antitumor T cells
,” Proc. Natl. Acad. Sci. U. S. A.
103
(35
), 13132
–13137
(2006
).22.
K. V.
Sivak
, A. V.
Vasin
, V. V.
Egorov
, V. B.
Tsevtkov
, N. N.
Kuzmich
, V. A.
Savina
, and O. I.
Kiselev
, “Adenosine A2A receptor as a drug target for treatment of sepsis
,” Mol. Biol.
50
(2
), 200
–212
(2016
).23.
T.
Matsumoto
, M.
Sakari
, M.
Okada
, A.
Yokoyama
, S.
Takahashi
, A.
Kouzmenko
, and S.
Kato
, “The androgen receptor in health and disease
,” Annu. Rev. Physiol.
75
(1
), 201
–224
(2013
).24.
Y.
Yuza
, K. A.
Glatt
, J.
Jiang
, H.
Greulich
, Y.
Minami
, M. S.
Woo
, T.
Shimamura
, G. I.
Shapiro
, J. C.
Lee
, and H.
Ji
, “Allele-dependent variation in the relative cellular potency of distinct EGFR inhibitors
,” Cancer Biol. Ther.
6
(5
), 661
–667
(2007
).25.
M.
De Vivo
, M.
Masetti
, G.
Bottegoni
, and A.
Cavalli
, “Role of molecular dynamics and related methods in drug discovery
,” J. Med. Chem.
59
(9
), 4035
–4061
(2016
).26.
M. C. R.
Melo
, R. C.
Bernardi
, C.
De La Fuente-Nunez
, and Z.
Luthey-Schulten
, “Generalized correlation-based dynamical network analysis: A new high-performance approach for identifying allosteric communications in molecular dynamics trajectories
,” J. Chem. Phys.
153
(13
), 134104
(2020
).27.
S.
Majumdar
, F.
Di Palma
, F.
Spyrakis
, S.
Decherchi
, and A.
Cavalli
, “Molecular dynamics and machine learning shed light on the flexibility-activity relationships in tyrosine kinome
” (unpublished).28.
K.
Lindorff‐Larsen
, S.
Piana
, K.
Palmo
, P.
Maragakis
, J. L.
Klepeis
, R. O.
Dror
, and D. E.
Shaw
, “Improved side‐chain torsion potentials for the Amber ff99SB protein force field
,” Proteins: Struct., Funct., Bioinf.
78
(8
), 1950
–1958
(2010
).29.
W. L.
Jorgensen
, J.
Chandrasekhar
, J. D.
Madura
, R. W.
Impey
, and M. L.
Klein
, “Comparison of simple potential functions for simulating liquid water
,” J. Chem. Phys.
79
(2
), 926
–935
(1983
).30.
S.
Decherchi
, G.
Bottegoni
, A.
Spitaleri
, W.
Rocchia
, and A.
Cavalli
, “BiKi Life sciences: A new suite for molecular dynamics and related methods in drug discovery
,” J. Chem. Inf. Model.
58
(2
), 219
–224
(2018
).31.
M. J.
Abraham
, T.
Murtola
, R.
Schulz
, S.
Páll
, J. C.
Smith
, B.
Hess
, and E.
Lindahl
, “GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers
,” SoftwareX
1-2
, 19
–25
(2015
).32.
S.
Decherchi
and W.
Rocchia
, “A general and robust ray-casting-based algorithm for triangulating surfaces at the nanoscale
,” PLoS One
8
(4
), e59744
(2013
).33.
T.
Mühlethaler
, D.
Gioia
, A. E.
Prota
, M. E.
Sharpe
, A.
Cavalli
, and M. O.
Steinmetz
, “Comprehensive analysis of binding sites in tubulin
,” Angew. Chem. Int. Ed.
60
, 13331
–13342
(2021
).34.
O. F.
Lange
and H.
Grubmüller
, “Generalized correlation for biomolecular dynamics
,” Proteins: Struct., Funct., Bioinf.
62
(4
), 1053
–1061
(2006
).35.
M.
Girvan
and M. E. J.
Newman
, “Community structure in social and biological networks
,” Proc. Natl. Acad. Sci. U. S. A.
99
(12
), 7821
–7826
(2002
).36.
R. W.
Floyd
, “On ambiguity in phrase structure languages
,” Commun. ACM
5
(10
), 526
(1962
).37.
I.
Rivalta
and V. S.
Batista
, Allostery
(Springer
, 2021
), pp. 137
–151
.38.
C.
Sanchez-Martin
, E.
Moroni
, M.
Ferraro
, C.
Laquatra
, G.
Cannino
, I.
Masgras
, A.
Negro
, P.
Quadrelli
, A.
Rasola
, and G.
Colombo
, “Rational design of allosteric and selective inhibitors of the molecular chaperone TRAP1
,” Cell Rep.
31
(3
), 107531
(2020
).39.
A.
Hagberg
, P.
Swart
, and D. S.
Chult
, Exploring Network Structure, Dynamics, and Function Using NetworkX, Los Alamos National Laboratory (LANL), Los Alamos, NM, USA
, 2008
.40.
G. H.
Golub
and C. F.
Van Loan
, Matrix Computations
(Johns Hopkins Baltimore MD
, 1983
).41.
D.
Kozakov
, L. E.
Grove
, D. R.
Hall
, T.
Bohnuud
, S. E.
Mottarella
, L.
Luo
, B.
Xia
, D.
Beglov
, and S.
Vajda
, “The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins
,” Nat. Protoc.
10
(5
), 733
–755
(2015
).42.
A. D.
Caliman
, Y.
Miao
, and J. A.
McCammon
, “Mapping the allosteric sites of the A2A adenosine receptor
,” Chem. Biol. Drug Des.
91
(1
), 5
–16
(2018
).43.
W.
Liu
, E.
Chun
, A. A.
Thompson
, P.
Chubukov
, F.
Xu
, V.
Katritch
, G. W.
Han
, C. B.
Roth
, L. H.
Heitman
, and A. P.
IJzerman
, “Structural basis for allosteric regulation of GPCRs by sodium ions
,” Science
337
(6091
), 232
–236
(2012
).44.
H.
Gutiérrez-de-Terán
, A.
Massink
, D.
Rodríguez
, W.
Liu
, G. W.
Han
, J. S.
Joseph
, I.
Katritch
, L. H.
Heitman
, L.
Xia
, and A. P.
IJzerman
, “The role of a sodium ion binding site in the allosteric modulation of the A2A adenosine G protein-coupled receptor
,” Structure
21
(12
), 2175
–2185
(2013
).45.
P.
Axerio-Cilies
, N. A.
Lack
, M. R. S.
Nayana
, K. H.
Chan
, A.
Yeung
, E.
Leblanc
, E. S. T.
Guns
, P. S.
Rennie
, and A.
Cherkasov
, “Inhibitors of androgen receptor activation function-2 (AF2) site identified through virtual screening
,” J. Med. Chem.
54
(18
), 6197
–6205
(2011
).46.
Y.
Qiu
, X.
Yin
, X.
Li
, Y.
Wang
, Q.
Fu
, R.
Huang
, and S.
Lu
, “Untangling dual-targeting therapeutic mechanism of epidermal growth factor receptor (EGFR) based on reversed allosteric communication
,” Pharmaceutics
13
(5
), 747
(2021
).47.
Z.
Zhao
, L.
Xie
, and P. E.
Bourne
, “Insights into the binding mode of MEK type-III inhibitors. A step towards discovering and designing allosteric kinase inhibitors across the human kinome
,” PLoS One
12
(6
), e0179936
(2017
).48.
N.
Otter
, M. A.
Porter
, U.
Tillmann
, P.
Grindrod
, and H. A.
Harrington
, “A roadmap for the computation of persistent homology
,” EPJ Data Sci.
6
, 17
(2017
).49.
J. P.
Arcon
, L. A.
Defelipe
, C. P.
Modenutti
, E. D.
López
, D.
Alvarez-Garcia
, X.
Barril
, A. G.
Turjanski
, and M. A.
Martí
, “Molecular dynamics in mixed solvents reveals protein–ligand interactions, improves docking, and allows accurate binding free energy predictions
,” J. Chem. Inf. Model.
57
(4
), 846
–863
(2017
).© 2023 Author(s). Published under an exclusive license by AIP Publishing.
2023
Author(s)
You do not currently have access to this content.