Towards Computational Modeling of Ligand Binding to the ILPR G-Quadruplex

Xiaotong Zhang, John Barrow, Tanja van Mourik*, Michael Bühl*

*Corresponding author for this work

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Using a combination of unconstrained and constrained molecular dynamics simulations, we have evaluated the binding affinities between two porphyrin derivatives (TMPyP4 and TEGPy) and the G-quadruplex (G4) of a DNA fragment modeling the insulin-linked polymorphic region (ILPR). Refining a well-established potential of mean force (PMF) approach to selections of constraints based on root-mean-square fluctuations results in an excellent agreement between the calculated and observed absolute free binding energy of TMPyP4. The binding affinity of IPLR-G4 toward TEGPy is predicted to be higher than that toward TMPyP4 by 2.5 kcal/mol, which can be traced back to stabilization provided by the polyether side chains of TMPyP4 that can nestle into the grooves of the quadruplex and form hydrogen bonds through the ether oxygen atoms. Because our refined methodology can be applied to large ligands with high flexibility, the present research opens an avenue for further ligand design in this important area.
Original languageEnglish
Article number3447
Number of pages14
Issue number8
Publication statusPublished - 13 Apr 2023

Bibliographical note

X.Z. wants to thank the Chinese Scholarship Council for funding. We thank EaStCHEM and the School of Chemistry for their support. Computations were carried out on the St Andrews HPC cluster and computer clusters in the School of Chemistry.
This research received no external funding.

Data Availability Statement

The research data supporting this publication can be accessed at (accessed on 1 April 2023).


  • G-quadruplex
  • Potential of mean force
  • Ligand with high flexibility


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