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

Xiaotong Zhang; John Barrow; Tanja van Mourik; Michael Bühl

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

Medical Education

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Abstract

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 language	English
Article number	3447
Number of pages	14
Journal	Molecules
Volume	28
Issue number	8
Publication status	Published - 13 Apr 2023

Bibliographical note

Acknowledgments
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.
Funding
This research received no external funding.

Data Availability Statement

The research data supporting this publication can be accessed at https://doi.org/10.17630/9505b210-dfec-401c-b32d-9151ae3810e3 (accessed on 1 April 2023).

Keywords

G-quadruplex
Potential of mean force
Ligand with high flexibility

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title = "Towards Computational Modeling of Ligand Binding to the ILPR G-Quadruplex",

abstract = "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.",

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author = "Xiaotong Zhang and John Barrow and {van Mourik}, Tanja and Michael B{\"u}hl",

note = "Acknowledgments 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. Funding This research received no external funding.",

year = "2023",

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T1 - Towards Computational Modeling of Ligand Binding to the ILPR G-Quadruplex

AU - Zhang, Xiaotong

AU - Barrow, John

AU - van Mourik, Tanja

AU - Bühl, Michael

N1 - Acknowledgments 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. Funding This research received no external funding.

PY - 2023/4/13

Y1 - 2023/4/13

N2 - 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.

AB - 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.

KW - G-quadruplex

KW - Potential of mean force

KW - Ligand with high flexibility

M3 - Article

SN - 1420-3049

VL - 28

JO - Molecules

JF - Molecules

IS - 8

M1 - 3447

ER -

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

Abstract

Bibliographical note

Data Availability Statement

Keywords

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