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

Area of Science:

• Molecular dynamics simulations
• Biophysics
• Computational chemistry

Background:

• G-quadruplex DNA structures, particularly the insulin-linked polymorphic region (ILPR), are implicated in various genetic disorders.
• Porphyrin derivatives are investigated as potential therapeutic agents targeting G-quadruplex DNA.

Purpose of the Study:

• To evaluate the binding affinities of two porphyrin derivatives, TMPyP4 and TEGPy, to the ILPR G-quadruplex.
• To refine and validate a molecular dynamics simulation methodology for predicting ligand-G4 binding energies.
• To provide insights into the molecular interactions governing the binding of these ligands to the G-quadruplex.

Main Methods:

• Utilized a combination of unconstrained and constrained molecular dynamics simulations.
• Employed a refined potential of mean force (PMF) approach, incorporating root-mean-square fluctuation-based constraint selections.
• Modeled a DNA fragment representing the insulin-linked polymorphic region (ILPR) G-quadruplex.

Main Results:

• Achieved excellent agreement between calculated and observed absolute free binding energy for TMPyP4.
• Predicted a higher binding affinity for TEGPy compared to TMPyP4 by 2.5 kcal/mol.
• Identified stabilization contributions from TEGPy's polyether side chains through interactions within the G-quadruplex grooves.

Conclusions:

• The refined simulation methodology accurately predicts binding energies for porphyrin derivatives with G-quadruplex DNA.
• TEGPy exhibits a stronger binding affinity to the ILPR G-quadruplex than TMPyP4.
• The study provides a robust computational framework for designing novel ligands targeting G-quadruplex structures.