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Molecular Simulation of Stapled Peptides

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Computational Peptide Science

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2405))

Abstract

Constrained peptides represent a relatively new class of biologic therapeutics, which have the potential to overcome several limitations of small-molecule drugs, and of designed antibodies. Because of their modest size, the rational design of such peptides is becoming increasingly amenable to computer simulation; multi-microsecond molecular dynamic (MD) simulations are now routinely possible on consumer-grade graphical processors (GPUs). Here, we describe the procedures for performing and analyzing MD simulations of hydrocarbon-stapled peptides using the CHARMM energy function, in isolation and in complex with a binding partner, to investigate their conformational properties and to compute changes in their binding affinity upon mutation.

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References

  1. Fosgerau K, Hoffmann T (2015) Peptide therapeutics: current status and future directions. Drug Discov Today 20(1):122–128. https://doi.org/10.1016/j.drudis.2014.10.003

    Article  CAS  Google Scholar 

  2. Cornillie S, Bruno B, Lim C, Cheatham T (2018) Computational modeling of stapled peptides toward a treatment strategy for CML and broader implications in the design of lengthy peptide therapeutics. J Phys chemistry B 122(14):3864–3875. https://doi.org/10.1021/acs.jpcb.8b01014

    Article  CAS  Google Scholar 

  3. Verdine GL, Hilinski GJ (2012) Stapled peptides for intracellular drug targets., vol 503, 1st edn. Elsevier Inc., Amsterdam. https://doi.org/10.1016/B978-0-12-396962-0.00001-X

    Google Scholar 

  4. Friedrichs M, Eastman P, Vaidyanathan V, Houston M, Legrand S, Beberg A, Ensign D, Bruns C, Pande V (2009) Accelerating molecular dynamic simulation on graphics processing units. J Comput Chem 30:864–872

    Article  CAS  Google Scholar 

  5. Brooks B, Brooks III C, Mackerell Jr A, Nilsson L, Petrella R, Roux B, Won Y, Archontis G, Bartels C, Boresch S, et al (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30:1545–1614, pMC2810661

    Google Scholar 

  6. Humphrey W, Dalke A, Schulten K (1996) VMD - visual molecular dynamics. J Mol Graphics 14:33–38

    Article  CAS  Google Scholar 

  7. McGibbon R, Beauchamp K, Harrigan M, Klein C, Swails J, Hernãndez C, Schwantes C, Wang L, Lane T, Pande V (2015) MDTraj: a modern open library for the analysis of molecular dynamics trajectories. Biophys J 109(8):1528–1532. https://doi.org/10.1016/j.bpj.2015.08.015

    Article  CAS  Google Scholar 

  8. (2020) CHARMM development project. https://charmm.chemistry.harvard.edu. Accessed 25 Dec 2020

  9. (2020) CHARMM force field. https://mackerell.umaryland.edu/charmm_ff.shtml. Accessed 25 Dec 2020

  10. (2020) Visual molecular dynamics. https://www.ks.uiuc.edu/Research/vmd/. Accessed 25 Dec 2020

  11. (2020) OpenMM. http://openmm.org. Accessed 25 Dec 2020

    Google Scholar 

  12. (2020) MDTraj. http://mdtraj.org. Accessed 25 Dec 2020

    Google Scholar 

  13. Eaton JW, Bateman D, Hauberg S, Wehbring R (2015) GNU octave version 4.0.0 manual: a high-level interactive language for numerical computations. http://www.gnu.org/software/octave/doc/interpreter

  14. Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel R, Kale L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802

    Article  CAS  Google Scholar 

  15. Best R, Zhu X, Shim J, Lopes P, Mittal J, Feig M, MacKerell Jr A (2012) Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone ϕ, ψ and side-chain χ1 and χ2 dihedral angles. J Chem Theor Comput 8:3257–3273

    Google Scholar 

  16. Guvench O, Mallajosyula S, Raman E, Hatcher E, Vanommeslaeghe K, Foster T, Jamison F, Mackerell A (2011) CHARMM additive all-atom force field for carbohydrate derivatives and its utility in polysaccharide and carbohydrate-protein modeling. J Chem Theor Comput 7(10):3162–3180. https://doi.org/10.1021/ct200328p

    Article  CAS  Google Scholar 

  17. Pearlman DA, Case DA, Caldwell JW, Ross WS, Cheatham TE, DeBolt S, Ferguson D, Seibel G, Kollman P (1995) Amber, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules. Comput Phys Commun 91(1):1–41. https://doi.org/10.1016/0010-4655(95)00041-D. http://www.sciencedirect.com/science/article/pii/001046559500041D

  18. Shivakumar D, Harder E, Damm W, Friesner RA, Sherman W (2012) Improving the prediction of absolute solvation free energies using the next generation OPLS force field. J Chem Theory Comput 8(8):2553–2558. https://doi.org/10.1021/ct300203w

    Article  CAS  Google Scholar 

  19. 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 Theor Comput 4(3):435–447. https://doi.org/10.1021/ct700301q. http://pubs.acs.org/doi/pdf/10.1021/ct700301q

  20. Brown CJ, Quah ST, Jong J, Goh AM, Chiam PC, Khoo KH, Choong ML, Lee Ma, Yurlova L, Zolghadr K, Joseph TL, Verma CS, Lane DP (2013) Stapled peptides with improved potency and specificity that activate P53. ACS Chem Biol 8(3):506–512. https://doi.org/10.1021/cb3005148

    Article  CAS  Google Scholar 

  21. Morrone J, Perez A, Deng Q, Ha S, Holloway M, Sawyer T, Sherborne B, Brown F, Dill K (2017) Molecular simulations identify binding poses and approximate affinities of stapled α-helical peptides to MDM2 and MDMX. J Chem Theor Comput 13(2):863–869. https://doi.org/10.1021/acs.jctc.6b00978

    Article  CAS  Google Scholar 

  22. Baek S, Kutchukian PS, Verdine GL, Huber R, Holak Ta, Lee KW, Popowicz GM (2012) Structure of the stapled P53 peptide bound to MDM2. J Am Chem Soc 134(1):103–106. https://doi.org/10.1021/ja2090367

    Article  CAS  Google Scholar 

  23. Ovchinnikov V, Stone TA, Deber C, Karplus M (2018) Structure of the EmrE multidrug transporter and its use for inhibitor peptide design. Proc Natl Acad Sci USA 115(34):E7942

    Article  Google Scholar 

  24. Frenkel D, Smit B (2001) Understanding molecular simulation: from algorithms to applications, 2nd edn. Academic, San Diego

    Google Scholar 

  25. Allen MP, Tildesley DJ (1989) Computer simulation of liquids. Clarendon Press, New York, NY

    Google Scholar 

  26. Rapaport DC (1996) The art of molecular dynamics simulation. Cambridge University Press, New York, NY

    Google Scholar 

  27. Onufriev A, Bashford D, Case D (2004) Exploring protein native states and large-scale conformational changes with a modified Generalized Born model. Proteins 55(2):383–394. https://doi.org/10.1002/prot.20033

    Article  CAS  Google Scholar 

  28. MATLAB (2010) Version 7.10.0 (R2010a). The MathWorks Inc., Natick, MA

    Google Scholar 

  29. Hazel A, Chipot C, Gumbart J (2014) Thermodynamics of deca-alanine folding in water. J Chem Theor Comput 10(7):2836–2844. https://doi.org/10.1021/ct5002076

    Article  CAS  Google Scholar 

  30. Chang Y, Graves B, Guerlavais V, Tovar C, Packman K, To K, Olson K, Kesavan K, Gangurde P, Mukherjee A, Baker T, Darlak K, Elkin C, Filipovic Z, Qureshi F, Cai H, Berry P, Feyfant E, Shi X, Horstick J, Annis D, Manning A, Fotouhi N, Nash H, Vassilev L, Sawyer T (2013) Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci USA 110(36):E3445–3454. https://doi.org/10.1073/pnas.1303002110

    Article  CAS  Google Scholar 

  31. Brice A, Dominy B (2011) Analyzing the robustness of the MM/PBSA free energy calculation method: application to DNA conformational transitions. J Comput Chem 32(2):1431–1440

    Article  CAS  Google Scholar 

  32. Srinivasan J, Cheatham TE, Cieplak P, Kollman PA, Case DA (1998) Continuum solvent studies of the stability of DNA, RNA, and phosphoramidate–DNA helices. J Am Chem Soc 120(37):9401–9409

    Article  CAS  Google Scholar 

  33. Ovchinnikov V, Cecchini M, Karplus M (2013) A simplified confinement method (SCM) for calculating absolute free energies and free energy and entropy differences. J Phys Chem B 117:750–762. https://doi.org/10.1021/jp3080578. pMC3569517

    Article  CAS  Google Scholar 

  34. Brooks B, Janežič D, Karplus M (1995) Harmonic analysis of large systems. I. Methodology. J Comput Chem 16:1522–1542

    Article  CAS  Google Scholar 

  35. Im W, Feig M, Brooks III C (2003) An implicit membrane generalized Born theory for the study of structure, stability, and interactions of membrane proteins. Biophys J 85:2900–2918

    Article  CAS  Google Scholar 

  36. Shirts M (2012) Best practices in free energy calculations for drug design. Methods Mol Biol 819:425–467. https://doi.org/10.1007/978-1-61779-465-0_26

    Article  CAS  Google Scholar 

  37. Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, Darwin E, Guvench O, Lopes P, Vorobyev I, MacKerell Jr A (2009) CHARMM general force field: a force field and drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem 31:671–690

    Google Scholar 

  38. Mayne CG, Saam J, Schulten K, Tajkhorshid E, Gumbart JC (2013) Rapid parameterization of small molecules using the force field toolkit. J Comput Chem 34(32):2757–2770. https://doi.org/10.1002/jcc.23422

    Article  CAS  Google Scholar 

  39. Simonson T, Roux B (2016) Concepts and protocols for electrostatic free energies. Mol Simul 42(13):1090–1101. https://doi.org/10.1080/08927022.2015.1121544

    Article  CAS  Google Scholar 

  40. Ryckaert JP, Ciccotti G, Berendsen H (1977) Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327–341

    Article  CAS  Google Scholar 

  41. Eswar N, Webb B, Marti-Renom M, Madhusudhan M, Eramian D, Shen M, Pieper U, Sali A (2006) Comparative protein structure modeling using modeller. Curr Prot Bioinf 54:5.6.1–5.6.37. https://doi.org/10.1002/0471250953.bi0506s15

    Google Scholar 

  42. Leaver-Fay A, Tyka M, Lewis S, Lange O, Thompson J, Jacak R, Kaufman K, Renfrew P, Smith C, Sheffler W, Davis I, Cooper S, Treuille A, Mandell D, Richter F, Ban Y, Fleishman S, Corn J, Kim D, Lyskov S, Berrondo M, Mentzer S, Popović Z, Havranek J, Karanicolas J, Das R, Meiler J, Kortemme T, Gray J, Kuhlman B, Baker D, Bradley P (2011) Rosetta3: an object-oriented software suite for the simulation and design of macromolecules. Methods Enzymol 487:545–574. https://doi.org/10.1016/B978-0-12-381270-4.00019-6

    Article  CAS  Google Scholar 

  43. Li L, Li C, Sarkar S, Zhang J, Witham S, Zhang Z, Wang L, Smith N, Petukh M, Alexov E (2012) DelPhi: a comprehensive suite for DelPhi software and associated resources. BMC Biophysics 5:9. https://doi.org/10.1186/2046-1682-5-9

    Article  Google Scholar 

  44. Roux B (1997) Influence of the membrane potential on the free energy of an intrinsic protein. Biophys J 73:2980–2989

    Article  CAS  Google Scholar 

  45. Baker N, Sept D, Joseph S, Holst M, McCammon J (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci USA 98:10037–10041

    Article  CAS  Google Scholar 

  46. Zoubir AM, Boashash B (1998) The bootstrap and its application in signal processing. IEEE Signal Process Mag 15(1):56–76. https://doi.org/10.1109/79.647043

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    Victor Ovchinnikov & Aravinda Munasinghe

  2. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    Martin Karplus

  3. Laboratoire de Chimie Biophysique, ISIS, Université de Strasbourg, Strasbourg, France

    Martin Karplus

Authors
  1. Victor Ovchinnikov
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  2. Aravinda Munasinghe
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  3. Martin Karplus
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Corresponding authors

Correspondence to Victor Ovchinnikov or Martin Karplus .

Editor information

Editors and Affiliations

  1. Lab de Biologie Structurale de la Cellule (CNRS UMR7654), Ecole Polytechnique, Palaiseau, France

    Thomas Simonson

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Ovchinnikov, V., Munasinghe, A., Karplus, M. (2022). Molecular Simulation of Stapled Peptides. In: Simonson, T. (eds) Computational Peptide Science. Methods in Molecular Biology, vol 2405. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1855-4_14

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  • DOI: https://doi.org/10.1007/978-1-0716-1855-4_14

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1854-7

  • Online ISBN: 978-1-0716-1855-4

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