Rate Constants and Mechanisms of Protein-Ligand Binding

Overview

Journal Annu Rev Biophys

Publisher Annual Reviews

Specialty Biophysics

Date 2017 Apr 5

PMID 28375732

Citations 21

Authors

Xiaodong Pang

Huan-Xiang Zhou

Affiliations

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Abstract

Whereas protein-ligand binding affinities have long-established prominence, binding rate constants and binding mechanisms have gained increasing attention in recent years. Both new computational methods and new experimental techniques have been developed to characterize the latter properties. It is now realized that binding mechanisms, like binding rate constants, can and should be quantitatively determined. In this review, we summarize studies and synthesize ideas on several topics in the hope of providing a coherent picture of and physical insight into binding kinetics. The topics include microscopic formulation of the kinetic problem and its reduction to simple rate equations; computation of binding rate constants; quantitative determination of binding mechanisms; and elucidation of physical factors that control binding rate constants and mechanisms.

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References

Held M, Metzner P, Prinz J, Noe F . Mechanisms of protein-ligand association and its modulation by protein mutations. Biophys J. 2011; 100(3):701-710. PMC: 3030248. DOI: 10.1016/j.bpj.2010.12.3699. View

Koh C, Kim J, Shibata S, Ranade R, Yu M, Liu J . Distinct states of methionyl-tRNA synthetase indicate inhibitor binding by conformational selection. Structure. 2012; 20(10):1681-91. PMC: 3472110. DOI: 10.1016/j.str.2012.07.011. View

Clore G . Interplay between conformational selection and induced fit in multidomain protein-ligand binding probed by paramagnetic relaxation enhancement. Biophys Chem. 2013; 186:3-12. PMC: 3944927. DOI: 10.1016/j.bpc.2013.08.006. View

Plattner N, Noe F . Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models. Nat Commun. 2015; 6:7653. PMC: 4506540. DOI: 10.1038/ncomms8653. View

Faradjian A, Elber R . Computing time scales from reaction coordinates by milestoning. J Chem Phys. 2004; 120(23):10880-9. DOI: 10.1063/1.1738640. View

Zhou H . From induced fit to conformational selection: a continuum of binding mechanism controlled by the timescale of conformational transitions. Biophys J. 2010; 98(6):L15-7. PMC: 2849054. DOI: 10.1016/j.bpj.2009.11.029. View

Schreiber G, Haran G, Zhou H . Fundamental aspects of protein-protein association kinetics. Chem Rev. 2009; 109(3):839-60. PMC: 2880639. DOI: 10.1021/cr800373w. View

Dogan J, Gianni S, Jemth P . The binding mechanisms of intrinsically disordered proteins. Phys Chem Chem Phys. 2013; 16(14):6323-31. DOI: 10.1039/c3cp54226b. View

Zhou H, Wlodek S, McCammon J . Conformation gating as a mechanism for enzyme specificity. Proc Natl Acad Sci U S A. 1998; 95(16):9280-3. PMC: 21329. DOI: 10.1073/pnas.95.16.9280. View

10.

Bernat B, Sun M, Dwyer M, Feldkamp M, Kossiakoff A . Dissecting the binding energy epitope of a high-affinity variant of human growth hormone: cooperative and additive effects from combining mutations from independently selected phage display mutagenesis libraries. Biochemistry. 2004; 43(20):6076-84. DOI: 10.1021/bi036069b. View

11.

Kiefhaber T, Bachmann A, Steen Jensen K . Dynamics and mechanisms of coupled protein folding and binding reactions. Curr Opin Struct Biol. 2011; 22(1):21-9. DOI: 10.1016/j.sbi.2011.09.010. View

12.

Jomain J, Tallet E, Broutin I, Hoos S, van Agthoven J, Ducruix A . Structural and thermodynamic bases for the design of pure prolactin receptor antagonists: X-ray structure of Del1-9-G129R-hPRL. J Biol Chem. 2007; 282(45):33118-31. DOI: 10.1074/jbc.M704364200. View

13.

Wade R, Gabdoulline R, Ludemann S, Lounnas V . Electrostatic steering and ionic tethering in enzyme-ligand binding: insights from simulations. Proc Natl Acad Sci U S A. 1998; 95(11):5942-9. PMC: 34177. DOI: 10.1073/pnas.95.11.5942. View

14.

Gianni S, Dogan J, Jemth P . Distinguishing induced fit from conformational selection. Biophys Chem. 2014; 189:33-9. DOI: 10.1016/j.bpc.2014.03.003. View

15.

Formaneck M, Ma L, Cui Q . Reconciling the "old" and "new" views of protein allostery: a molecular simulation study of chemotaxis Y protein (CheY). Proteins. 2006; 63(4):846-67. DOI: 10.1002/prot.20893. View

16.

Sines J, Allison S, McCammon J . Point charge distributions and electrostatic steering in enzyme/substrate encounter: Brownian dynamics of modified copper/zinc superoxide dismutases. Biochemistry. 1990; 29(40):9403-12. DOI: 10.1021/bi00492a014. View

17.

Changeux J, Edelstein S . Conformational selection or induced fit? 50 years of debate resolved. F1000 Biol Rep. 2011; 3:19. PMC: 3169905. DOI: 10.3410/B3-19. View

18.

Rogers J, Oleinikovas V, Shammas S, Wong C, De Sancho D, Baker C . Interplay between partner and ligand facilitates the folding and binding of an intrinsically disordered protein. Proc Natl Acad Sci U S A. 2014; 111(43):15420-5. PMC: 4217413. DOI: 10.1073/pnas.1409122111. View

19.

Wade R, Davis M, Luty B, Madura J, McCammon J . Gating of the active site of triose phosphate isomerase: Brownian dynamics simulations of flexible peptide loops in the enzyme. Biophys J. 1993; 64(1):9-15. PMC: 1262297. DOI: 10.1016/S0006-3495(93)81335-3. View

20.

Greives N, Zhou H . BDflex: a method for efficient treatment of molecular flexibility in calculating protein-ligand binding rate constants from brownian dynamics simulations. J Chem Phys. 2012; 137(13):135105. PMC: 3477184. DOI: 10.1063/1.4756913. View