Molecular Dynamics Simulations of Conformational Conversions in Transformer Proteins

  • Bernard S. GerstmanEmail author
  • Prem P. Chapagain
  • Jeevan GC
  • Timothy Steckmann
Part of the Methods in Molecular Biology book series (MIMB, volume 1958)


A relatively recently discovered class of proteins known as transformer proteins undergo large-scale conformational conversions that change their supersecondary structure. These structural transformations lead to different configurations that perform different functions. We describe computational methods using molecular dynamics simulations that allow the determination of the specific amino acids that facilitate the conformational transformations. These investigations provide guidance on the location and type of amino acid mutations that can either enhance or inhibit the structural transitions that allow transformer proteins to perform multiple functions.

Key words

Transformer proteins Molecular dynamics Amyloid Ebola VP40 


  1. 1.
    Knauer SH, Artsimovitch I, Rösch P (2012) Transformer proteins. Cell Cycle 11:4289–4290CrossRefGoogle Scholar
  2. 2.
    GC JB, Bhandari YR, Gerstman BS, Chapagain PP (2014) Molecular dynamics investigations of the α-helix to β-barrel conformational transformation in the RfaH transcription factor. J Phys Chem B 118:5101–5108CrossRefGoogle Scholar
  3. 3.
    Zhou M, Ottenberg G, Sferrazza GF, Lasmezas CI (2012) Highly neurotoxic monomeric alpha-helical prion protein. Proc Natl Acad Sci U S A 109:3113–3118CrossRefGoogle Scholar
  4. 4.
    Eisenberg D, Jucker M (2012) The amyloid state of proteins in human diseases. Cell 148:1188–1203CrossRefGoogle Scholar
  5. 5.
    Straub JE, Thirumalai D (2011) Toward a molecular theory of early and late events in monomer to amyloid fibril formation. Annu Rev Phys Chem 62:437–463CrossRefGoogle Scholar
  6. 6.
    Brundin P, Melki R, Kopito R (2010) Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol 11:301–307CrossRefGoogle Scholar
  7. 7.
    DeMarco ML, Daggett V (2004) From conversion to aggregation: protofibril formation of the prion protein. Proc Natl Acad Sci U S A 101:2293–2298CrossRefGoogle Scholar
  8. 8.
    Diaz-Espinoza R, Soto C (2012) High-resolution structure of infectious prion protein: the final frontier. Nat Struct Mol Biol 19:370–377CrossRefGoogle Scholar
  9. 9.
    Huang L, Jin R, Li J, Luo K, Huang T, Wu D, Wang W, Chen R, Xiao G (2010) Macromolecular crowding converts the human recombinant PrPC to the soluble neurotoxic β-oligomers. FASEB J 24:3536–3543CrossRefGoogle Scholar
  10. 10.
    Sang JC, Lee CY, Luh FY, Huang YW, Chiang YW, Chen RP (2012) Slow spontaneous alpha-to-beta structural conversion in a non-denaturing neutral condition reveals the intrinsically disordered property of the disulfide-reduced recombinant mouse prion protein. Prion 6:489–497CrossRefGoogle Scholar
  11. 11.
    Khandogin J, Brooks CL 3rd (2007) Linking folding with aggregation in Alzheimer’s beta-amyloid peptides. Proc Natl Acad Sci U S A 104:16880–16885CrossRefGoogle Scholar
  12. 12.
    Steckmann T, Awan Z, Gerstman BS, Chapagain PP (2012) Kinetics of peptide secondary structure conversion during amyloid beta-protein fibrillogenesis. J Theor Biol 301:95–102CrossRefGoogle Scholar
  13. 13.
    Kammerer RA, Kostrewa D, Zurdo J, Detken A, Garcia-Echeverria C, Green JD, Muller SA, Meier BH, Winkler FK, Dobson CM et al (2004) Exploring amyloid formation by a de novo design. Proc Natl Acad Sci U S A 101:4435–4440CrossRefGoogle Scholar
  14. 14.
    Steinmetz MO, Gattin Z, Verel R, Ciani B, Stromer T, Green JM, Tittmann P, Schulze-Briese C, Gross H, van Gunsteren WF et al (2008) Atomic models of de novo designed cc beta-Met amyloid-like fibrils. J Mol Biol 376:898–912CrossRefGoogle Scholar
  15. 15.
    Woolfson DN, Ryadnov MG (2006) Peptide-based fibrous biomaterials: some things old, new and borrowed. Curr Opin Chem Biol 10:559–567CrossRefGoogle Scholar
  16. 16.
    Ding F, Borreguero JM, Buldyrey SV, Stanley HE, Dokholyan NV (2003) mechanism for the alpha-helix to beta-hairpin transition. Proteins 53:220–228CrossRefGoogle Scholar
  17. 17.
    Hansen MB, Ruizendaal L, Löwik DWPM, van Hest JCM (2009) Switchable peptides. Drug Discov Today Technol 6:e33–e39CrossRefGoogle Scholar
  18. 18.
    Qin Z, Buehler MJ (2010) Molecular dynamics simulation of the α-helix to β-sheet transition in coiled protein filaments: evidence for a critical filament length scale. Phys Rev Lett 104:198304CrossRefGoogle Scholar
  19. 19.
    Wang X, Bergenfeld I, Arora PS, Canary JW (2012) Reversible redox reconfiguration of secondary structures in a designed peptide. Angew Chem Int Ed Eng 51:2099–13101Google Scholar
  20. 20.
    Yoon S, Welsh WJ (2005) Rapid assessment of contact-dependent secondary structure propensity: relevance to amyloidogenic sequences. Proteins 60:110–117CrossRefGoogle Scholar
  21. 21.
    Burmann BM, Knauer SH, Sevostyanova A, Schweimer K, Mooney RA, Landick R, Artsimovitch I, Rosch P (2012) An alpha helix to beta-barrel domain switch transforms the transcription factor RfaH into a translation factor. Cell 150:291–303CrossRefGoogle Scholar
  22. 22.
    GC JB, Gerstman BS, Chapagain PP (2015) The role of the interdomain interactions on RfaH dynamics and conformational transformation. J Phys Chem B 119(40):12750–12759CrossRefGoogle Scholar
  23. 23.
    Svetlov V, Nudler E (2012) Unfolding the bridge between transcription and translation. Cell 150:243–245CrossRefGoogle Scholar
  24. 24.
    Eswar N, Webb B, Marti-Renom MA, Madhusudhan MS, Eramian D, Shen MY, Pieper U, Sali A (2006) Comparative protein structure modeling using Modeller. Curr Protoc Bioinformatics Chapter 5:Unit 5.6Google Scholar
  25. 25.
    Sanchez R, Sali A (2000) Comparative protein structure modeling. Introduction and practical examples with modeller. Methods Mol Biol 143:97–129PubMedGoogle Scholar
  26. 26.
    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38CrossRefGoogle Scholar
  27. 27.
    Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, Darian E, Guvench O, Lopes P, Vorobyov I, Mackerell AD Jr (2010) CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem 31:671–690PubMedPubMedCentralGoogle Scholar
  28. 28.
    Rao F, Caflisch A (2003) Replica exchange molecular dynamics simulations of reversible folding. J Chem Phys 119(7):4035–4042CrossRefGoogle Scholar
  29. 29.
    Zhang W, Wu C, Duan Y (2005) Convergence of replica exchange molecular dynamics. J Chem Phys 123(15):154105CrossRefGoogle Scholar
  30. 30.
    Martin HS, Jha S, Coveney PV (2014) Comparative analysis of nucleotide translocation through protein nanopores using steered molecular dynamics and an adaptive biasing force. J Comput Chem 35:692–702CrossRefGoogle Scholar
  31. 31.
    Steckmann T, Bhandari YR, Chapagain PP, Gerstman BS (2017) Cooperative structural transitions in amyloid-like aggregation. J Chem Phys 146:135103CrossRefGoogle Scholar
  32. 32.
    Isralewitz B, Gao M, Schulten K (2001) Steered molecular dynamics and mechanical functions of proteins. Curr Opin Struct Biol 11:224–230CrossRefGoogle Scholar
  33. 33.
    Phillips JC, Braun R, 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 26:1781–1802CrossRefGoogle Scholar
  34. 34.
    Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Bernard S. Gerstman
    • 1
    Email author
  • Prem P. Chapagain
    • 1
  • Jeevan GC
    • 1
  • Timothy Steckmann
    • 1
  1. 1.Department of PhysicsFlorida International UniversityMiamiUSA

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