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Peer-reviewedCC BYThe journal of physical chemistry letters

Binding Does Not Mean Stabilizing: High-Affinity Porphyrins Exhibit Opposite Effects on G-Quadruplex Stability.

  • Cristina Carucci1
  • Monica Mura1
  • Francesca Cherchi1
  • Giuseppe Satta2
  • Aamir Saeed1
  • Barbara Jachimska3
  • Francesca Mocci1
  • Massimo Carraro2
  • Andrea Salis1
  1. 1Department of Chemical and Geological Sciences, University of Cagliari & CSGI, Cittadella Universitaria, S.S. 554 bivio Sestu, 09042Monserrato (Cagliari), Italy.
  2. 2Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, Via Vienna 2, Sassari07100, Italy.
  3. 3Jerzy Haber Institute of Catalysis and Surface Chemistry Polish Academy of Sciences, Krakow30-239, Poland.
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Abstract

Binding affinity is often used as a predictor of G-quadruplex (G4) stabilization. Here, we show that ligand binding and quadruplex stabilization can be thermodynamically decoupled. Two closely related tetracationic porphyrins bind the human telomeric G4 with comparable affinities approaching 106 M-1 but induce opposite thermal responses. TMPyP4 stabilizes the quadruplex (+9 °C), whereas PL7 destabilizes it (-6 °C) despite a similar binding free energy. Thermodynamic analysis reveals distinct binding mechanisms, with TMPyP4 association driven primarily by favorable enthalpy and PL7 binding dominated by entropy. Temperature-dependent circular dichroism measurements indicate that PL7 promotes redistribution within the telomeric G4 conformational ensemble rather than stabilization of the native hybrid fold. These findings demonstrate that high affinity does not necessarily imply G4 stabilization and establish affinity and thermal stabilization as independent descriptors of ligand-quadruplex interactions.

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Cite

BibTeXRIS
BibTeX
@article{carucci2026binding,
  title = {{Binding Does Not Mean Stabilizing: High-Affinity Porphyrins Exhibit Opposite Effects on G-Quadruplex Stability.}},
  author = {Cristina Carucci and Monica Mura and Francesca Cherchi and Giuseppe Satta and Aamir Saeed and Barbara Jachimska and Francesca Mocci and Massimo Carraro and Andrea Salis},
  journal = {The journal of physical chemistry letters},
  year = {2026},
  month = sep,
  doi = {10.1021/acs.jpclett.6c02493},
  url = {https://europepmc.org/article/MED/42917869},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Binding Does Not Mean Stabilizing: High-Affinity Porphyrins Exhibit Opposite Effects on G-Quadruplex Stability.
AU  - Cristina Carucci
AU  - Monica Mura
AU  - Francesca Cherchi
AU  - Giuseppe Satta
AU  - Aamir Saeed
AU  - Barbara Jachimska
AU  - Francesca Mocci
AU  - Massimo Carraro
AU  - Andrea Salis
PY  - 2026
DA  - 2026/09/01
JO  - The journal of physical chemistry letters
DO  - 10.1021/acs.jpclett.6c02493
UR  - https://europepmc.org/article/MED/42917869
AB  - Binding affinity is often used as a predictor of G-quadruplex (G4) stabilization. Here, we show that ligand binding and quadruplex stabilization can be thermodynamically decoupled. Two closely related tetracationic porphyrins bind the human telomeric G4 with comparable affinities approaching 106 M-1 but induce opposite thermal responses. TMPyP4 stabilizes the quadruplex (+9 °C), whereas PL7 destabilizes it (-6 °C) despite a similar binding free energy. Thermodynamic analysis reveals distinct binding mechanisms, with TMPyP4 association driven primarily by favorable enthalpy and PL7 binding dominated by entropy. Temperature-dependent circular dichroism measurements indicate that PL7 promotes redistribution within the telomeric G4 conformational ensemble rather than stabilization of the native hybrid fold. These findings demonstrate that high affinity does not necessarily imply G4 stabilization and establish affinity and thermal stabilization as independent descriptors of ligand-quadruplex interactions.
SN  - 1948-7185
ER  -