2D-IR spectroscopy shows that optimised DNA minor groove binding of Hoechst33258 follows an induced fit model

Lennart A. I. Ramakers; Gordon Hithell; John J. May; Gregory M. Greetham; Paul M. Donaldson; Michael Towrie; Anthony W. Parker; Glenn Burley; Neil Hunt

doi:10.1021/acs.jpcb.7b00345

2D-IR spectroscopy shows that optimised DNA minor groove binding of Hoechst33258 follows an induced fit model

Lennart A. I. Ramakers, Gordon Hithell, John J. May, Gregory M. Greetham, Paul M. Donaldson, Michael Towrie, Anthony W. Parker, Glenn Burley, Neil Hunt

Research output: Contribution to journal › Article

11 Citations (Scopus)

Abstract

The induced fit binding model describes a conformational change occurring when a small molecule binds to its biomacromolecular target. The result is enhanced non-covalent interactions between ligand and biomolecule. Induced fit is well-established for small molecule-protein interactions, but its relevance to small molecule-DNA binding is less clear. We investigate the molecular determinants of Hoechst33258 binding to its preferred A-tract sequence relative to a sub-optimal alternating A-T sequence. Results from 2-dimensional infrared spectroscopy, which is sensitive to H-bonding and molecular structure changes, show that Hoechst33258 binding results in loss of minor groove spine of hydration in both sequences, but an additional perturbation of the base propeller twists occurs in the A-tract binding region. This induced fit maximizes favourable ligand-DNA enthalpic contributions in the optimal binding case and demonstrates that controlling the molecular details that induce subtle changes in DNA structure may hold the key to designing next-generation DNA-binding molecules.

Language	English
Journal	Journal of Physical Chemistry B
Early online date	19 Jan 2017
DOIs	10.1021/acs.jpcb.7b00345
Publication status	E-pub ahead of print - 19 Jan 2017

Fingerprint

grooves

Infrared spectroscopy

DNA

deoxyribonucleic acid

Molecules

spectroscopy

Ligands

Biomolecules

Propellers

molecules

Hydration

Molecular structure

ligands

propellers

spine

Proteins

determinants

hydration

molecular structure

infrared spectroscopy

Keywords

spectroscopy
DNA
Hoechst33258
minor groove binding
induced fit
non-covalent interactions
ligand
biomolecule
molecule-DNA binding

Cite this

Ramakers, L. A. I., Hithell, G., May, J. J., Greetham, G. M., Donaldson, P. M., Towrie, M., ... Hunt, N. (2017). 2D-IR spectroscopy shows that optimised DNA minor groove binding of Hoechst33258 follows an induced fit model. Journal of Physical Chemistry B. https://doi.org/10.1021/acs.jpcb.7b00345

Ramakers, Lennart A. I. ; Hithell, Gordon ; May, John J. ; Greetham, Gregory M. ; Donaldson, Paul M. ; Towrie, Michael ; Parker, Anthony W. ; Burley, Glenn ; Hunt, Neil. / 2D-IR spectroscopy shows that optimised DNA minor groove binding of Hoechst33258 follows an induced fit model. In: Journal of Physical Chemistry B. 2017.

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title = "2D-IR spectroscopy shows that optimised DNA minor groove binding of Hoechst33258 follows an induced fit model",

abstract = "The induced fit binding model describes a conformational change occurring when a small molecule binds to its biomacromolecular target. The result is enhanced non-covalent interactions between ligand and biomolecule. Induced fit is well-established for small molecule-protein interactions, but its relevance to small molecule-DNA binding is less clear. We investigate the molecular determinants of Hoechst33258 binding to its preferred A-tract sequence relative to a sub-optimal alternating A-T sequence. Results from 2-dimensional infrared spectroscopy, which is sensitive to H-bonding and molecular structure changes, show that Hoechst33258 binding results in loss of minor groove spine of hydration in both sequences, but an additional perturbation of the base propeller twists occurs in the A-tract binding region. This induced fit maximizes favourable ligand-DNA enthalpic contributions in the optimal binding case and demonstrates that controlling the molecular details that induce subtle changes in DNA structure may hold the key to designing next-generation DNA-binding molecules.",

keywords = "spectroscopy, DNA, Hoechst33258, minor groove binding, induced fit, non-covalent interactions, ligand, biomolecule, molecule-DNA binding",

author = "Ramakers, {Lennart A. I.} and Gordon Hithell and May, {John J.} and Greetham, {Gregory M.} and Donaldson, {Paul M.} and Michael Towrie and Parker, {Anthony W.} and Glenn Burley and Neil Hunt",

note = "“This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Physical Chemistry B, copyright {\circledC} American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acs.jpcb.7b00345.",

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Ramakers, LAI, Hithell, G, May, JJ, Greetham, GM, Donaldson, PM, Towrie, M, Parker, AW, Burley, G & Hunt, N 2017, '2D-IR spectroscopy shows that optimised DNA minor groove binding of Hoechst33258 follows an induced fit model' Journal of Physical Chemistry B. https://doi.org/10.1021/acs.jpcb.7b00345

2D-IR spectroscopy shows that optimised DNA minor groove binding of Hoechst33258 follows an induced fit model. / Ramakers, Lennart A. I.; Hithell, Gordon; May, John J.; Greetham, Gregory M.; Donaldson, Paul M.; Towrie, Michael; Parker, Anthony W.; Burley, Glenn; Hunt, Neil.

In: Journal of Physical Chemistry B, 19.01.2017.

Research output: Contribution to journal › Article

TY - JOUR

T1 - 2D-IR spectroscopy shows that optimised DNA minor groove binding of Hoechst33258 follows an induced fit model

AU - Ramakers, Lennart A. I.

AU - Hithell, Gordon

AU - May, John J.

AU - Greetham, Gregory M.

AU - Donaldson, Paul M.

AU - Towrie, Michael

AU - Parker, Anthony W.

AU - Burley, Glenn

AU - Hunt, Neil

N1 - “This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Physical Chemistry B, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acs.jpcb.7b00345.

PY - 2017/1/19

Y1 - 2017/1/19

N2 - The induced fit binding model describes a conformational change occurring when a small molecule binds to its biomacromolecular target. The result is enhanced non-covalent interactions between ligand and biomolecule. Induced fit is well-established for small molecule-protein interactions, but its relevance to small molecule-DNA binding is less clear. We investigate the molecular determinants of Hoechst33258 binding to its preferred A-tract sequence relative to a sub-optimal alternating A-T sequence. Results from 2-dimensional infrared spectroscopy, which is sensitive to H-bonding and molecular structure changes, show that Hoechst33258 binding results in loss of minor groove spine of hydration in both sequences, but an additional perturbation of the base propeller twists occurs in the A-tract binding region. This induced fit maximizes favourable ligand-DNA enthalpic contributions in the optimal binding case and demonstrates that controlling the molecular details that induce subtle changes in DNA structure may hold the key to designing next-generation DNA-binding molecules.

AB - The induced fit binding model describes a conformational change occurring when a small molecule binds to its biomacromolecular target. The result is enhanced non-covalent interactions between ligand and biomolecule. Induced fit is well-established for small molecule-protein interactions, but its relevance to small molecule-DNA binding is less clear. We investigate the molecular determinants of Hoechst33258 binding to its preferred A-tract sequence relative to a sub-optimal alternating A-T sequence. Results from 2-dimensional infrared spectroscopy, which is sensitive to H-bonding and molecular structure changes, show that Hoechst33258 binding results in loss of minor groove spine of hydration in both sequences, but an additional perturbation of the base propeller twists occurs in the A-tract binding region. This induced fit maximizes favourable ligand-DNA enthalpic contributions in the optimal binding case and demonstrates that controlling the molecular details that induce subtle changes in DNA structure may hold the key to designing next-generation DNA-binding molecules.

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