Abstract—The capabilities of computer analysis of the conformational properties of proteins and the nature of their interactions with ligands are rapidly growing due to the development of molecular modeling methods and advances in computer technology. Despite this, the existing theoretical methods are still far from ideal and their predictions require experimental verification. Therefore, accurate experimental methods for measuring the parameters of interaction between proteins and small molecules are in high demand to address both fundamental and applied issues, such as the study of intracellular processes and the creation of new drugs. In this review, we consider three well-proven modern biophysical techniques for the determination of the affinity, stoichiometry, and energy of the interaction of proteins with ligands: isothermal titration calorimetry, microscale thermophoresis, and surface plasmon resonance. Particular attention is paid to the development of the technical capabilities of these methods in recent years, the intricacies of their practical use, and illustrations of their application to solve specific biophysical problems in pharmacology.
Similar content being viewed by others
REFERENCES
G. Kapoor, S. Saigal, and A. Elongavan, J. Anaesthesiol. Clin. Pharmacol. 33 (3), 300 (2017).
W. P. Walters and M. Namchuk, Nat. Rev. Drug Discov. 2 (4), 259 (2003).
J. Hughes, S. Rees, S. Kalindjian, and K. Philpott, Br. J. Pharmacol. 162 (6), 1239 (2011).
T. Wiseman, S. Williston, J. F. Brandts, and L.-N. Lin, Anal. Biochem. 179 (1), 131 (1989).
C. J. Wienken, P. Baaske, U. Rothbauer, et al., Nat. Commun. 1 (7), 100 (2010).
M. Raghavan and P. J. Bjorkman, Structure 1993, 3 (4), 331 (1995).
P. W. Atkins and J. De Paula, Physical Chemistry for the Life Sciences, 2nd ed. (Freeman, New York; Oxford Univ. Press, Oxford, 2011).
D. G. Myszka, Y. N. Abdiche, F. Arisaka, et al., J. Biomol. Tech. 14 (4), 247 (2003).
G. A. Holdgate and W. H. J. Ward, Drug Discov. Today 10 (22), 1543 (2005).
J. J. Christensen, R. M. Izatt, L. D. Hansen, and J. A. Partridge, J. Phys. Chem. 70 (6), 2003 (1966).
N. V. Beaudette and N. Langerman, Anal. Biochem. 90 (2), 693 (1978).
J. C. Martinez, J. Murciano-Calles, E. S. Cobos, et al., in Applications of Calorimetry in a Wide Context: Differential Scanning Calorimetry, Isothermal Titration Calorimetry and Microcalorimetry, Ed. by A. A. Elkordy (Intech, Croatia, 2013), Ch. 4, pp. 74–104.
M. M. Pierce, C. S. Raman, and B. T. Nall, Methods 19 (2), 213 (1999).
Protein-Ligand Interactions: Methods and Applications, 2nd ed., Ed. by M. A. Williams and T. Daviter (Humana Press, Springer, New York, 2013).
J. A. Liberman, J. T. Bogue, J. L. Jenkins, M. Salim, and J. E. Wedekind, Methods Enzymol. 549, 435 (2014).
L. Kraft, L. Serpell, and J. Atack, Biomolecules 9 (2), 48 (2019).
S. Nagatoishi, et al., Bioorg. Med. Chem. 26 (8), 1929 (2018).
D. Wu, et al., Haematologica 103 (9), 1472 (2018).
C. Ludwig, Diffusion zwischen ungleich erwärmten Orten gleich zusammengesetzter Lösung (Aus der K.K. Hofund Staatsdruckerei, in Commission bei W. Braumuller, Buchhandler des K. K. Hofes und der K. Akademie der Wissenschaften, Wien, 1856).
S. Duhr and D. Braun, Proc. Natl. Acad. Sci. U. S. A. 103 (52), 19678 (2006).
M. Wolff, E. Nicholls1, A. M. Reynolds, et al., Sci. Rep. 6 (1), 32612 (2016). https://doi.org/10.1038/srep32612
M. Reichl, M. Herzog, A. Gotz, and D. Braun, Phys. Rev. Lett. 112 (19), 198101 (2014).
P. Baaske, C. J. Wienken, P. Reineck, et al., Angew. Chem. Int. Ed. 49 (12), 2238 (2010).
C. P. Toseland, J. Chem. Biol. 6 (3), 85 (2013).
M. M. Baksh, A. K. Kussrow, M. Mileni, et al., Nat. Biotechnol. 29 (4), 357 (2011).
V. Ratner, E. Kahana, M. Eichler, and E. Haas, Bioconjug. Chem. 13 (5), 1163 (2002).
S. A. I. Seidel, C. J. Wienken, S. Geissler, et al., Angew. Chem. Int. Ed., 51 (42), 10656 (2012).
S. A. I. Seidel, P. M. Dijkman, W. A. Lea, et al., Methods 59 (3), 301 (2013).
T. H. Scheuermann, S. B. Padrick, K. H. Gardner, and C. A. Brautigam, Anal. Biochem. 496, 79 (2016).
C. Entzian and T. Schubert, J. Vis. Exp. 119, 55070 (2017). https://doi.org/10.3791/55070
T. Rogez-Florent, L. Duhamel, L. Goossens, et al., J. Mol. Recognit. 27 (1), 46 (2014).
T. Rogez-Florent, C. Foulon, A. S. Drucbert, et al., J. Pharm. Biomed. Anal. 137, 113 (2017).
M. van de Weert and L. Stella, J. Mol. Struct. 998 (1), 144 (2011).
P. R. Callis and T. Liu, J. Phys. Chem. B 108 (14), 4248 (2004).
J. R. Lakowicz, Principles of Fluorescence Spectroscopy, 3rd ed. (Springer, 2006).
M. Jerabek-Willemsen, T. Andre, R, Wanner, et al., J. Mol. Struct. 1077, 101 (2014).P
S.-C. Tso, Q. Chen, S. A. Vishnivetskiy, et al., Anal. Biochem. 540–541, 64 (2018).
B. Liedberg, C. Nylander, and I. Lunstrom, Sens. Actuators 4, 299 (1983).
R. L. Rich and D. G. Myszka, J. Mol. Recognit. 14 (4), 223 (2001).
B. Johnsson, S. Lofas, G. Lindquist, et al., J. Mol. Recognit. 8 (1–2), 125 (1995).
B. Johnsson, S. Lofas, and G. Lindquist, Anal. Biochem. 198 (2), 268 (1991).
Y. S. N. Day, C. L. Baird, R. L. Rich, and D. G. Myszka, Prot. Sci. Publ. Prot. Soc. 11 (5), 1017 (2002).
P. Schuck and H. Zhao, Methods Mol. Biol. 627, 15 (2010).
D. G. Myszka, X. He, M. Dembo, et al., Biophys. J. 75 (2), 583 (1998).
45. J.-P. Renaud, C. W. Chung, U. H. Danielson, et al., Nat. Rev. Drug Discov. 15 (10), 679 (2016).
M. Ui and K. Tsumoto, Recent Pat. Biotechnol. 4 (3), 183 (2010).
V. Linkuviene, G. Krainer, W.-Y. Chen, and D. Matulis, Anal. Biochem. 515, 61 (2016).
I. Y. Petrushanko, V. M. Lobachev, A. S. Kononikhin, et al., PloS One 11 (7), e0158726 (2016).
S.-J. Lin, Y.-F. Chen, K.-Ch. Hsu, et al., Toxins 11 (4), 233 (2019).
P. O. Tsvetkov, A. A. Makarov, S. Malesinski, et al., Biochimie 94 (3), 916 (2012).
E. H. Mashalidis, P. Śledź, S. Lang, and C. Abell, Nat. Protoc. 8 (11), 2309 (2013).
J. Cramer, S. G. Krimmer, A. Heine, and G. Klebe, J. Med. Chem. 60 (13), 5791 (2017).
P. O. Tsvetkov, A. A. Kulikova, F. Devred, et al., Mol. Biol. (Moscow) 45 (4), 641 (2011).
M. K. Zia, T. Siddiqui, S. S. Ali, et al., Int. J. Biol. Macromol. 133, 1081 (2019).
W. Du, et al., J. Biol. Chem., Apr. (2019).
M. Amaral, D. B. Kokh, J. Bomke, et al., Nat. Commun. 8 (1), 2276 (2017).
Q. Dan, W. Xiong, H. Liang, et al., Food Res. Int. 120, 255 (2019).
J. D. Chodera and D. L. Mobley, Annu. Rev. Biophys. 42, 121 (2013).
T. J. Wyckoff, C. R. Raetz, and J. E. Jackman, Trends Microbiol. 6 (4), 154 (1998).
J. M. Clements, F. Coignard, I. Johnson, et al., Antimicrob. Agents Chemother. 46 (6), 1793 (2002).
M. C. Pirrung, L. N. Tumey, C. R. H. Raetz, et al., J. Med. Chem. 45 (19), 4359 (2002).
X. Du, Y. Li, Y.-L. Xia, et al., Int. J. Mol. Sci. 17 (2), 144 (2016).
M. Asmari, R. Ratih, H. A. Alhazmi, and S. El Deeb, Methods 146, 107 (2018).
A. M. Mueller, D. Breitsprecher, S. Duhr, et al., Methods Mol. Biol. 1654, 151 (2017).
P. Reineck, C. J. Wienken, and D. Braun, Electrophoresis 31 (2), 279 (2010).
E. Fisher, Y. Zhao, R. Richerdson, et al., ACS Chem. Neurosci. 8 (9), 2088 (2017).
S. A. Khmeleva, Y. V. Mezentsev, S. A. Kozin, et al., Mol. Biol. (Moscow) 49 (3), 450 (2015).
F. O. Tsvetkov, A. A. Makarov, A. I. Archakov, and S. A. Kozin, Biophysics (Moscow) 54 (2), 131 (2009).
L. M. F. Gomes, et al., Chem. Sci. 10 (6), 1634 (2018).
C. Cheignon, et al., Chem. Sci. 8 (7), 5107 (2017).
S. A. Khmeleva, et al., J. Alzheimer’s Dis. 54 (2), 809 (2016).
F. Wu, T. Song, Y. Yao, and Y. Song, PloS One 14 (5), e0216203 (2019).
S. Zeng, D. Baillargeat, H.-P. Ho, and K.-T. Yong, Chem. Soc. Rev. 43 (10), 3426 (2014).
E. Fabini and U. H. Danielson, J. Pharm. Biomed. Anal. 144, 188 (2017).
A. Meneghello, S. Tartaggia, M. D. Alvau, et al., Curr. Med. Chem. 25 (34), 4354 (2018).
R. Mowla, Y. Wang, S. Ma, and H. Venter, Biochim. Biophys. Acta – Biomembranes 1860 (4), 878 (2018).
P. Taghipour, M. Zakariazadeh, M. Sharifi, et al., J. Photochem. Photobiol. B 183, 11 (2018).
D. G. Drescher, D. Selvakumar, and M. J. Drescher, in Advances in Protein Chemistry and Structural Biology, 110, Ed. by R. Donev (Academic Press, 2018), pp. 1–30.
M. F. Rollins, J. T. Schuman, K. Paulus, et al., Nucleic Acids Res. 43 (4), 2216 (2015).
L. Dai, et al., Cell Host Microbe 19 (5), 696 (2016).
X. Meng, R. Deng, X. Zhu, and Z. Zhang, Virol. J. 15 (1), 21 (2018).
E. Wallin and G. von Heijne, Prot. Sci. Publ. Prot. Soc. 7 (4), 1029 (1998).
L. Fagerberg, K. Jonasson, G. von Heijne, et al., Proteomics 10 (6), 1141 (2010).
S. G. Patching, Biochim. Biophys. Acta 1838 (1, Pt. A), 43 (2014).
C. Rechlin, et al., ACS Chem. Biol. 12 (5), 1397 (2017).
Funding
This work was supported by the Russian Science Foundation, project no. 17-74-20152.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The authors declare that they have no conflict of interest. This article does not contain any studies involving animals or human participants performed by any of the authors.
Additional information
Translated by E. Puchkov
Abbreviations: ITC, isothermal titration calorimetry; MST, microscale thermophoresis; SPR, surface plasmon resonance; LpxC, uridine diphosphate-3-O-acyl-N-acetylglucosamine acetylase.
Rights and permissions
About this article
Cite this article
Korshunova, A.V., Lopanskaia, I.N. & Gudimchuk, N.B. Modern Approaches to Analysis of Protein–Ligand Interactions. BIOPHYSICS 64, 495–509 (2019). https://doi.org/10.1134/S0006350919040079
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0006350919040079