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

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G-Quadruplex Nucleic Acids

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2035))

Abstract

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.

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References

  1. Siddiqui-Jain A, Grand CL, Bearss DJ, Hurley LH (2002) Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc Natl Acad Sci 99(18):11593–11598. https://doi.org/10.1073/pnas.182256799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yang D, Okamoto K (2010) Structural insights into G-quadruplexes: towards new anticancer drugs. Future Med Chem 2(4):619–646. https://doi.org/10.4155/fmc.09.172

    Article  CAS  PubMed  Google Scholar 

  3. Neidle S (2016) Quadruplex nucleic acids as novel therapeutic targets. J Med Chem 59(13):5987–6011. https://doi.org/10.1021/acs.jmedchem.5b01835

    Article  CAS  PubMed  Google Scholar 

  4. Hou JQ, Chen SB, Tan JH, Luo HB, Li D, Gu LQ, Huang ZS (2012) New insights from molecular dynamic simulation studies of the multiple binding modes of a ligand with G-quadruplex DNA. J Comput Aided Mol Des 26(12):1355–1368. https://doi.org/10.1007/s10822-012-9619-1

    Article  CAS  PubMed  Google Scholar 

  5. Dixon IM, Lopez F, Tejera AM, Esteve JP, Blasco MA, Pratviel G, Meunier B (2007) A G-quadruplex ligand with 10000-fold selectivity over duplex DNA. J Am Chem Soc 129(6):1502–1503. https://doi.org/10.1021/ja065591t

    Article  CAS  PubMed  Google Scholar 

  6. Hou J-Q, Chen S-B, Zan L-P, Ou T-M, Tan J-H, Luyt LG, Huang Z-S (2015) Identification of a selective G-quadruplex DNA binder using a multistep virtual screening approach. Chem Commun 51(1):198–201. https://doi.org/10.1039/C4CC06951J

    Article  CAS  Google Scholar 

  7. Ferreira RS, Simeonov A, Jadhav A, Eidam O, Mott BT, Keiser MJ, McKerrow JH, Maloney DJ, Irwin JJ, Shoichet BK (2010) Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors. J Med Chem 53(13):4891–4905. https://doi.org/10.1021/jm100488w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gilson M, Given J, Bush B, McCammon J (1997) The statistical-thermodynamic basis for computation of binding affinities: a critical review. Biophys J 72(3):1047–1069. https://doi.org/10.1016/S0006-3495(97)78756-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Boresch S, Tettinger F, Leitgeb M, Karplus M (2003) Absolute binding free energies: a quantitative approach for their calculation. J Phys Chem B 107(35):9535–9551. https://doi.org/10.1021/jp0217839

    Article  CAS  Google Scholar 

  10. Hamelberg D, McCammon JA (2004) Standard free energy of releasing a localized water molecule from the binding pockets of proteins: double-decoupling method. J Am Chem Soc 126(24):7683–7689. https://doi.org/10.1021/ja0377908

    Article  CAS  PubMed  Google Scholar 

  11. Woo HJ, Roux B (2005) Calculation of absolute protein-ligand binding free energy from computer simulations. Proc Natl Acad Sci 102(19):6825–6830. https://doi.org/10.1073/pnas.0409005102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Deng N, Forli S, He P, Perryman A, Wickstrom L, Vijayan SKV, Tiefenbrunn T, Stout CD, Gallicchio E, Olson AJ, Levy RM (2014) Distinguishing binders from false positives by free energy calculations: fragment screening against the flap site of HIV protease. J Phys Chem B 119(3):976–988. https://doi.org/10.1021/jp506376z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Deng N, Wickstrom L, Cieplak P, Lin C, Yang D (2017) Resolving the ligand-binding specificity in c-MYC G-quadruplex DNA: absolute binding free energy calculations and SPR experiment. J Phys Chem B 121(46):10484–10497. https://doi.org/10.1021/acs.jpcb.7b09406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Leach A (2001) Molecular modelling: principles and applications (2nd edition). Pearson, New York, NY

    Google Scholar 

  15. Lemkul J GROMACS Tutorial. http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/complex/index.html

  16. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4(3):435–447. https://doi.org/10.1021/ct700301q

    Article  CAS  PubMed  Google Scholar 

  17. Pronk S, Pall S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, Shirts MR, Smith JC, Kasson PM, van der Spoel D, Hess B, Lindahl E (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29(7):845–854. https://doi.org/10.1093/bioinformatics/btt055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mark Abraham BH, van der Spoel D, Lindahl E (2016) GROMACS Reference Manual

    Google Scholar 

  19. Case DSC DA, Cheatham TE III, Darden TA, Duke RE, Giese TJ, Gohlke H, Goetz AW, Greene D, Homeyer N, Izadi S, Kovalenko A, Lee TS, LeGrand S, Li P, Lin C, Liu J, Luchko T, Luo R, Mermelstein D, Merz KM, Monard G, Nguyen H, Omelyan I, Onufriev A, Pan F, Qi R, Roe DR, Roitberg A, Sagui C, Simmerling CL, Botello-Smith WM, Swails J, Walker RC, Wang J, Wolf RM, Wu X, Xiao L, York DM, Kollman PA (2017) AMBER 2017. University of California, San Francisco

    Google Scholar 

  20. James C, Phillips RB, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kale L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802. https://doi.org/10.1002/jcc.20289

    Article  CAS  Google Scholar 

  21. Brooks BR, Mackerell AD Jr, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, Woodcock HL, Wu X, Yang W, York DM, Karplus M (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30:1545–1614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Votapka LW, Jagger BR, Heyneman AL, Amaro RE (2017) SEEKR: simulation enabled estimation of kinetic rates, a computational tool to estimate molecular kinetics and its application to trypsin-benzamidine binding. J Phys Chem B 121(15):3597–3606. https://doi.org/10.1021/acs.jpcb.6b09388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shan Y, Kim ET, Eastwood MP, Dror RO, Seeliger MA, Shaw DE (2011) How does a drug molecule find its target binding site? J Am Chem Soc 133(24):9181–9183. https://doi.org/10.1021/ja202726y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Perrot P (1998) A to Z of thermodynamics. Oxford University Press, Oxford

    Google Scholar 

  25. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791. https://doi.org/10.1002/jcc.21256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47(7):1739–1749. https://doi.org/10.1021/jm0306430

    Article  CAS  PubMed  Google Scholar 

  27. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47(7):1750–1759. https://doi.org/10.1021/jm030644s

    Article  CAS  PubMed  Google Scholar 

  28. Lin C, Wu G, Wang K, Onel B, Sakai S, Shao Y, Yang D (2018) Molecular recognition of the hybrid-2 human telomeric G-quadruplex by epiberberine: insights into conversion of telomeric G-quadruplex structures. Angew Chem Int Ed Eng. https://doi.org/10.1002/anie.201804667

    Article  CAS  PubMed  Google Scholar 

  29. Luo D, Mu Y (2015) All-atomic simulations on human telomeric G-quadruplex DNA binding with thioflavin T. J Phys Chem B 119(15):4955–4967. https://doi.org/10.1021/acs.jpcb.5b01107

    Article  CAS  PubMed  Google Scholar 

  30. Mulholland K, Wu C (2016) Binding of telomestatin to a telomeric G-quadruplex DNA probed by all-atom molecular dynamics simulations with explicit solvent. J Chem Inf Model 56(10):2093–2102. https://doi.org/10.1021/acs.jcim.6b00473

    Article  CAS  PubMed  Google Scholar 

  31. Pérez A, Marchán I, Svozil D, Sponer J, Cheatham TE, Laughton CA, Orozco M (2007) Refinement of the AMBER force field for nucleic acids: improving the description of α/γ conformers. Biophys J 92(11):3817–3829. https://doi.org/10.1529/biophysj.106.097782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zgarbova M, Sponer J, Otyepka M, Cheatham TE 3rd, Galindo-Murillo R, Jurecka P (2015) Refinement of the sugar-phosphate backbone torsion beta for AMBER force fields improves the description of Z- and B-DNA. J Chem Theory Comput 11(12):5723–5736. https://doi.org/10.1021/acs.jctc.5b00716

    Article  CAS  PubMed  Google Scholar 

  33. ACPYPE. https://code.google.com/archive/p/acpype/

  34. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25(9):1157–1174. https://doi.org/10.1002/jcc.20035

    Article  CAS  PubMed  Google Scholar 

  35. Jakalian A, Bush BL, Jack DB, Bayly CI (2000) Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method. J Comput Chem 21(2):132–146. https://doi.org/10.1002/(SICI)1096-987X(20000130)21:2<132::AID-JCC5>3.0.CO;2-P

    Article  CAS  Google Scholar 

  36. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79(2):926. https://doi.org/10.1063/1.445869

    Article  CAS  Google Scholar 

  37. Joung IS, Cheatham TE (2008) Determination of alkali and halide monovalent ion parameters for use in explicitly solvated biomolecular simulations. J Phys Chem B 112(30):9020–9041. https://doi.org/10.1021/jp8001614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kästner J (2011) Umbrella sampling. Wiley Interdiscip Rev: Comput Mol Sci 1(6):932–942. https://doi.org/10.1002/wcms.66

    Article  CAS  Google Scholar 

  39. Gallicchio E, Andrec M, Felts AK, Levy RM (2005) Temperature weighted histogram analysis method, replica exchange, and transition paths†. J Phys Chem B 109(14):6722–6731. https://doi.org/10.1021/jp045294f

    Article  CAS  PubMed  Google Scholar 

  40. Kumar S, Rosenberg JM, Bouzida D, Swendsen RH, Kollman PA (1992) THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method. J Comput Chem 13(8):1011–1021. https://doi.org/10.1002/jcc.540130812

    Article  CAS  Google Scholar 

  41. Grossfield A WHAM. http://membrane.urmc.rochester.edu/sites/default/files/wham/doc.pdf

  42. Deng Y, Roux B (2006) Calculation of standard binding free energies: aromatic molecules in the T4 lysozyme L99A mutant. J Chem Theory Comput 2(5):1255–1273. https://doi.org/10.1021/ct060037v

    Article  CAS  PubMed  Google Scholar 

  43. Deng N, Zhang P, Cieplak P, Lai L (2011) Elucidating the energetics of entropically driven protein–ligand association: calculations of absolute binding free energy and entropy. J Phys Chem B 115(41):11902–11910. https://doi.org/10.1021/jp204047b

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zwanzig RW (1954) High-temperature equation of state by a perturbation method. I. Nonpolar gases. J Chem Phys 22(8):1420–1426. https://doi.org/10.1063/1.1740409

    Article  CAS  Google Scholar 

  45. Beutler TC, Mark AE, van Schaik RC, Gerber PR, van Gunsteren WF (1994) Avoiding singularities and numerical instabilities in free energy calculations based on molecular simulations. Chem Phys Lett 222(6):529–539. https://doi.org/10.1016/0009-2614(94)00397-1

    Article  CAS  Google Scholar 

  46. Rocklin GJ, Mobley DL, Dill KA, Hünenberger PH (2013) Calculating the binding free energies of charged species based on explicit-solvent simulations employing lattice-sum methods: an accurate correction scheme for electrostatic finite-size effects. J Chem Phys 139(18):184103. https://doi.org/10.1063/1.4826261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci 98(18):10037–10041. https://doi.org/10.1073/pnas.181342398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Deng N, Cui D, Zhang BW, Xia J, Cruz J, Levy R (2018) Comparing alchemical and physical pathway methods for computing the absolute binding free energy of charged ligands. Phys Chem Chem Phys 20(25):17081–17092. https://doi.org/10.1039/c8cp01524d

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dai J, Carver M, Hurley LH, Yang D (2011) Solution structure of a 2:1 quindoline–c-MYC G-quadruplex: insights into G-quadruplex-interactive small molecule drug design. J Am Chem Soc 133(44):17673–17680. https://doi.org/10.1021/ja205646q

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

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

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Authors and Affiliations

  1. Department of Chemistry and Physical Sciences, Pace University, New York, NY, USA

    Nanjie Deng

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  1. Nanjie Deng
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Editors and Affiliations

  1. Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, Purdue Center for Cancer Research, Purdue Institute for Drug Discovery, West Lafayette, IN, USA

    Danzhou Yang

  2. Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN, USA

    Clement Lin

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Deng, N. (2019). Using Molecular Dynamics Free Energy Simulation to Compute Binding Affinities of DNA G-Quadruplex Ligands. In: Yang, D., Lin, C. (eds) G-Quadruplex Nucleic Acids. Methods in Molecular Biology, vol 2035. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9666-7_10

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  • DOI: https://doi.org/10.1007/978-1-4939-9666-7_10

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9665-0

  • Online ISBN: 978-1-4939-9666-7

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