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

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-establ...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2023-04, Vol.28 (8), p.3447
Main Authors: Zhang, Xiaotong, Barrow, John, van Mourik, Tanja, Bühl, Michael
Format: Article
Language:English
Subjects:
Affinity
Analysis
Deoxyribonucleic acid
DNA
Energy
Equilibrium
Force and energy
G-quadruplex
G-Quadruplexes
Grooves
Hydrogen bonding
Hydrogen bonds
Insulin
Insulin - metabolism
ligand with high flexibility
Ligands
Molecular dynamics
Molecular Dynamics Simulation
Oxygen atoms
Polyethylene glycol
Porphyrins
Porphyrins - chemistry
potential of mean force
RNA polymerase
Simulation
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Summary: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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules28083447