Using Molecular Dynamics Free Energy Simulation to Compute Binding Affinities of DNA G-Quadruplex Ligands
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 doc
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Introduction The DNA G-quadruplex formed in the guanine-rich regions in human telomeres and gene promoters has been targeted for developing novel anticancer therapy [1–3]. The G-quadruplex interactive ligands often bind at the terminal G-tetrads but may also bind with the more flexible loops [4]. An important goal in structurebased drug discovery is to identify small molecules that have both high affinity and good selectivity for G-quadruplex over duplex DNA [5]. Computational methods such as docking have been used in virtual screening studies to discover potent G-quadruplex ligands with good affinity and selectivity [6]. However, the accuracy of docking can be limited by the relatively simple scoring functions employed, which lack adequate treatments of the ligand and binding site desolvation, receptor reorganization and entropy effect. As a result, virtual screening of ligand library by docking can result in high false positive rate [7].
Danzhou Yang and Clement Lin (eds.), G-Quadruplex Nucleic Acids: Methods and Protocols, Methods in Molecular Biology, vol. 2035, https://doi.org/10.1007/978-1-4939-9666-7_10, © Springer Science+Business Media, LLC, part of Springer Nature 2019
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Fig. 1 (a) The 2D structure of the quindoline derivative. (b) The NMR structure of the 2:1 quindoline-c-MYC G-quadruplex complex. The two quindoline molecules at the 50 -end and 30 end are shown in yellow and green sticks, respectively. At the 30 -end the intermolecular hydrogen bond between the T23O4 of the DNA and N1 of the quindoline is shown as green dashed line. The two potassium ions are shown as purple dots. (c) The sequence of c-MYC G-quadruplex (Myc 14/23)
Binding free energy methods such as the double decoupling method (DDM) [8–10] and the potential of mean force method (PMF) [11] are based on statistical mechanics and molecular dynamics simulations (MD) in explicit solvent, which can capture in principle the desolvation, receptor reorganization and entropic effects in binding. These more detailed methods can be employed as additional filters following docking to more accurately compute binding affinity and separate true binders from false positives. We have shown that the combination of docking and DDM can lead to significant improvement over docking alone for in silico ligand screening against an allosteric site on the HIV-1 Protease [12]. More recently, we have applied both DDM and PMF to compute the absolute binding free energy for a G-quadruplex DNA target [13]. The parallel DNA G-quadruplex formed in the c-MYC gene promoter regulates the c-MYC transcription. NMR revealed two drug binding sites located at the 50 and 30 termini of the c-MYC G-quadruplex. To determine the ligand binding site specificity in the c-MYC G-quadruplex, that is, which site is more favored in drug binding, we calculated the binding free energies for a quindoline derivative at each of the two binding sites in the G-quadruplex (Fig. 1). The calculated absolute binding free energies are in good agreement with the SPR determin
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