Using Molecular Dynamics Free Energy Simulation to Compute Binding Affinities of DNA G-Quadruplex Ligands

  • Nanjie Deng
Part of the Methods in Molecular Biology book series (MIMB, volume 2035)


We provide a practical guide for using molecular dynamics simulation to compute the binding affinity of small molecules in complex with G-quadruplex DNA. Such calculations have a number of applications, such as rescoring docking results and validating docked poses, to inform the discovery of G-quadruplex binders with high affinity and selectivity. This chapter describes two binding free energy protocols: the double decoupling method (DDM) and the potential of mean force method (PMF). We illustrate the application of the two methods using a recent case study of the binding of quindoline with the c-MYC G-quadruplex DNA. For this system, the two methods yield absolute binding free energies within ~2 kcal/mol of the experimental value. We discuss the advantages and disadvantages of these binding free energy methods.

Key words

Molecular dynamics simulation Absolute binding free energy Double decoupling method Potential of mean force c-MYC G-quadruplex Quindoline 



The author thanks Dr. Danzhou Yang, Dr. Piotr Cieplak, and Dr. Lauren Wickstrom for helpful discussions.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Nanjie Deng
    • 1
  1. 1.Department of Chemistry and Physical SciencesPace UniversityNew YorkUSA

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