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-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.

Automated summary

Using a combination of unconstrained and constrained molecular dynamics simulations, 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) were evaluated. The calculated and observed absolute free binding energy of TMPyP4 showed excellent agreement, thanks to the refined potential of mean force (PMF) approach. The study predicts a higher binding affinity of IPLR-G4 towards TEGPy, attributed to the stabilization provided by the polyether side chains of TMPyP4 through hydrogen bonding with the ether oxygen atoms.