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Interplay of halogen bonding and solvation in protein-ligand binding

Verteramo, Maria Luisa LU ; Ignjatović, Majda Misini ; Kumar, Rohit LU ; Wernersson, Sven LU ; Ekberg, Vilhelm LU ; Wallerstein, Johan LU ; Carlström, Göran LU orcid ; Chadimová, Veronika ; Leffler, Hakon LU and Zetterberg, Fredrik , et al. (2024) In iScience 27(4).
Abstract

Halogen bonding is increasingly utilized in efforts to achieve high affinity and selectivity of molecules designed to bind proteins, making it paramount to understand the relationship between structure, dynamics, and thermodynamic driving forces. We present a detailed analysis addressing this problem using a series of protein-ligand complexes involving single halogen substitutions - F, Cl, Br, and I - and nearly identical structures. Isothermal titration calorimetry reveals an increasingly favorable binding enthalpy from F to I that correlates with the halogen size and σ-hole electropositive character, but is partially counteracted by unfavorable entropy, which is constant from F to Cl and Br, but worse for I. Consequently, the binding... (More)

Halogen bonding is increasingly utilized in efforts to achieve high affinity and selectivity of molecules designed to bind proteins, making it paramount to understand the relationship between structure, dynamics, and thermodynamic driving forces. We present a detailed analysis addressing this problem using a series of protein-ligand complexes involving single halogen substitutions - F, Cl, Br, and I - and nearly identical structures. Isothermal titration calorimetry reveals an increasingly favorable binding enthalpy from F to I that correlates with the halogen size and σ-hole electropositive character, but is partially counteracted by unfavorable entropy, which is constant from F to Cl and Br, but worse for I. Consequently, the binding free energy is roughly equal for Cl, Br, and I. QM and solvation-free-energy calculations reflect an intricate balance between halogen bonding, hydrogen bonds, and solvation. These advances have the potential to aid future drug design initiatives involving halogenated compounds.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
iScience
volume
27
issue
4
article number
109636
publisher
Elsevier
external identifiers
  • pmid:38633000
  • scopus:85190154337
ISSN
2589-0042
DOI
10.1016/j.isci.2024.109636
language
English
LU publication?
yes
additional info
© 2024 The Author(s).
id
78431055-a775-441b-948f-e50331e3095b
date added to LUP
2024-04-18 16:09:07
date last changed
2025-03-23 16:37:15
@article{78431055-a775-441b-948f-e50331e3095b,
  abstract     = {{<p>Halogen bonding is increasingly utilized in efforts to achieve high affinity and selectivity of molecules designed to bind proteins, making it paramount to understand the relationship between structure, dynamics, and thermodynamic driving forces. We present a detailed analysis addressing this problem using a series of protein-ligand complexes involving single halogen substitutions - F, Cl, Br, and I - and nearly identical structures. Isothermal titration calorimetry reveals an increasingly favorable binding enthalpy from F to I that correlates with the halogen size and σ-hole electropositive character, but is partially counteracted by unfavorable entropy, which is constant from F to Cl and Br, but worse for I. Consequently, the binding free energy is roughly equal for Cl, Br, and I. QM and solvation-free-energy calculations reflect an intricate balance between halogen bonding, hydrogen bonds, and solvation. These advances have the potential to aid future drug design initiatives involving halogenated compounds.</p>}},
  author       = {{Verteramo, Maria Luisa and Ignjatović, Majda Misini and Kumar, Rohit and Wernersson, Sven and Ekberg, Vilhelm and Wallerstein, Johan and Carlström, Göran and Chadimová, Veronika and Leffler, Hakon and Zetterberg, Fredrik and Logan, Derek T. and Ryde, Ulf and Akke, Mikael and Nilsson, Ulf J.}},
  issn         = {{2589-0042}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{4}},
  publisher    = {{Elsevier}},
  series       = {{iScience}},
  title        = {{Interplay of halogen bonding and solvation in protein-ligand binding}},
  url          = {{http://dx.doi.org/10.1016/j.isci.2024.109636}},
  doi          = {{10.1016/j.isci.2024.109636}},
  volume       = {{27}},
  year         = {{2024}},
}