Advertisement

Hybrid Methods for Macromolecular Modeling by Molecular Mechanics Simulations with Experimental Data

  • Osamu Miyashita
  • Florence Tama
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1105)

Abstract

Hybrid approaches for the modeling of macromolecular complexes that combine computational molecular mechanics simulations with experimental data are discussed. Experimental data for biological molecular structures are often low-resolution, and thus, do not contain enough information to determine the atomic positions of molecules. This is especially true when the dynamics of large macromolecules are the focus of the study. However, computational modeling can complement missing information. Significant increase in computational power, as well as the development of new modeling algorithms allow us to model structures of biological macromolecules reliably, using experimental data as references. We review the basics of molecular mechanics approaches, such as atomic model force field, and coarse-grained models, molecular dynamics simulation and normal mode analysis and describe how they could be used for flexible fitting hybrid modeling with experimental data, especially from cryo-EM and SAXS.

Keywords

Cryo-EM SAXS Normal mode analysis Molecular dynamics simulations Coarse-grained models Fitting Modeling 

Notes

Acknowledgements

We thank Sandhya P. Tiwari and Ashutosh Srivastava for carefully reading the manuscript and providing comments. This work was supported by FOCUS for Establishing Supercomputing Center of Excellence, JSPS KAKENHI Grant Number 17K07305, 16K07286, 26119006, 15K21711 and RIKEN Dynamic Structural Biology Project.

References

  1. Ahmed A, Tama F (2013) Consensus among multiple approaches as a reliability measure for flexible fitting into cryo-EM data. J Struct Biol 182:67–77CrossRefGoogle Scholar
  2. Anami Y, Shimizu N, Ekimoto T, Egawa D, Itoh T, Ikeguchi M, Yamamoto K (2016) Apo- and antagonist-binding structures of vitamin D receptor ligand-binding domain revealed by hybrid approach combining small-angle X-ray scattering and molecular dynamics. J Med Chem 59:7888–7900CrossRefGoogle Scholar
  3. Barty A (2016) Single molecule imaging using X-ray free electron lasers. Curr Opin Struct Biol 40:186–194CrossRefGoogle Scholar
  4. Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The Amber biomolecular simulation programs. J Comput Chem 26:1668–1688CrossRefGoogle Scholar
  5. Chen PC, Hub JS (2015) Interpretation of solution x-ray scattering by explicit-solvent molecular dynamics. Biophys J 108:2573–2584CrossRefGoogle Scholar
  6. Dashti A, Schwander P, Langlois R, Fung R, Li W, Hosseinizadeh A, Liao HY, Pallesen J, Sharma G, Stupina VA, Simon AE, Dinman JD, Frank J, Ourmazd A (2014) Trajectories of the ribosome as a Brownian nanomachine. Proc Natl Acad Sci U S A 111:17492–17497CrossRefGoogle Scholar
  7. Frank J (2017) Advances in the field of single-particle cryo-electron microscopy over the last decade. Nat Protoc 12:209–212CrossRefGoogle Scholar
  8. Fritz BG, Roberts SA, Ahmed A, Breci L, Li W, Weichsel A, Brailey JL, Wysocki VH, Tama F, Montfort WR (2013) Molecular model of a soluble guanylyl cyclase fragment determined by small-angle X-ray scattering and chemical cross-linking. Biochemistry 52:1568–1582CrossRefGoogle Scholar
  9. Gallagher-Jones M, Rodriguez JA, Miao J (2016) Frontier methods in coherent X-ray diffraction for high-resolution structure determination. Q Rev Biophys 49Google Scholar
  10. Garman EF (2014) Developments in x-ray crystallographic structure determination of biological macromolecules. Science 343:1102–1108CrossRefGoogle Scholar
  11. Gorba C, Miyashita O, Tama F (2008) Normal-mode flexible fitting of high-resolution structure of biological molecules toward one-dimensional low-resolution data. Biophys J 94:1589–1599CrossRefGoogle Scholar
  12. Holdbrook DA, Burmann BM, Huber RG, Petoukhov MV, Svergun DI, Hiller S, Bond PJ (2017) A spring-loaded mechanism governs the clamp-like dynamics of the Skp chaperone. structure 25:1079–1088.e3CrossRefGoogle Scholar
  13. Huang J, Rauscher S, Nawrocki G, Ran T, Feig M, de Groot BL, Grubmüller H, MacKerell AD (2017) CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat Methods 14:71–73CrossRefGoogle Scholar
  14. Hub JS (2017) Interpreting solution X-ray scattering data using molecular simulations. Curr Opin Struct Biol 49:18–26CrossRefGoogle Scholar
  15. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph Model 14:33–38CrossRefGoogle Scholar
  16. Jin Q, Sorzano COS, de la Rosa-Trevín JM, Bilbao-Castro JR, Núñez-Ramírez R, Llorca O, Tama F, Jonić S (2014) Iterative elastic 3D-to-2D alignment method using normal modes for studying structural dynamics of large macromolecular complexes. Structure 22:496–506CrossRefGoogle Scholar
  17. Kikhney AG, Svergun DI (2015) A practical guide to small angle X-ray scattering (SAXS) of flexible and intrinsically disordered proteins. FEBS Lett 589:2570–2577CrossRefGoogle Scholar
  18. Kim DN, Sanbonmatsu KY (2017) Tools for the cryo-EM gold rush: going from the cryo-EM map to the atomistic model. Biosci Rep 37CrossRefGoogle Scholar
  19. Lander GC, Saibil HR, Nogales E (2012) Go hybrid: EM, crystallography, and beyond. Curr Opin Struct Biol 22:627–635CrossRefGoogle Scholar
  20. Liu H, Hexemer A, Zwart PH (2012) The Small Angle Scattering ToolBox(SASTBX): an open-source software for biomolecular small-angle scattering. J Appl Crystallogr 45:587–593CrossRefGoogle Scholar
  21. Lopéz-Blanco JR, Chacón P (2013) iMODFIT: efficient and robust flexible fitting based on vibrational analysis in internal coordinates. J Struct Biol 184:261–270CrossRefGoogle Scholar
  22. Louder RK, He Y, López-Blanco JR, Fang J, Chacón P, Nogales E (2016) Structure of promoter-bound TFIID and model of human pre-initiation complex assembly. Nature 531:604–609CrossRefGoogle Scholar
  23. Mahajan S, Sanejouand YH (2015) On the relationship between low-frequency normal modes and the large-scale conformational changes of proteins. Arch Biochem Biophys 567:59–65CrossRefGoogle Scholar
  24. McGreevy R, Teo I, Singharoy A, Schulten K (2016) Advances in the molecular dynamics flexible fitting method for cryo-EM modeling. Methods 100:50–60CrossRefGoogle Scholar
  25. Merzel F, Smith JC (2002) SASSIM: a method for calculating small-angle X-ray and neutron scattering and the associated molecular envelope from explicit-atom models of solvated proteins. Acta Crystallogr D Biol Crystallogr 58:242–249CrossRefGoogle Scholar
  26. Miao J, Ishikawa T, Robinson IK, Murnane MM (2015) Beyond crystallography: diffractive imaging using coherent x-ray light sources. Science 348:530–535CrossRefGoogle Scholar
  27. Mitra K, Schaffitzel C, Shaikh T, Tama F, Jenni S, Brooks CL, Ban N, Frank J (2005) Structure of the E. coli protein-conducting channel bound to a translating ribosome. Nature 438:318–324CrossRefGoogle Scholar
  28. Miyashita O, Joti Y (2017) X-ray free electron laser single-particle analysis for biological systems. Curr Opin Struct Biol 43:163–169CrossRefGoogle Scholar
  29. Miyashita O, Onuchic JN, Wolynes PG (2003) Nonlinear elasticity, proteinquakes, and the energy landscapes of functional transitions in proteins. Proc Natl Acad Sci U S A 100:12570–12575CrossRefGoogle Scholar
  30. Miyashita O, Kobayashi C, Mori T, Sugita Y, Tama F (2017) Flexible fitting to cryo-EM density map using ensemble molecular dynamics simulations. J Comput Chem 38:1447–1461CrossRefGoogle Scholar
  31. Nguyen HT, Pabit SA, Meisburger SP, Pollack L, Case DA (2014) Accurate small and wide angle x-ray scattering profiles from atomic models of proteins and nucleic acids. J Chem Phys 141:22D508CrossRefGoogle Scholar
  32. Oroguchi T, Ikeguchi M (2011) Effects of ionic strength on SAXS data for proteins revealed by molecular dynamics simulations. J Chem Phys 134:025102CrossRefGoogle Scholar
  33. Orzechowski M, Tama F (2008) Flexible fitting of high-resolution x-ray structures into cryoelectron microscopy maps using biased molecular dynamics simulations. Biophys J 95:5692–5705CrossRefGoogle Scholar
  34. Pelikan M, Hura G, Hammel M (2009) Structure and flexibility within proteins as identified through small angle X-ray scattering. Gen Physiol Biophys 28:174–189CrossRefGoogle Scholar
  35. Perilla JR, Goh BC, Cassidy CK, Liu B, Bernardi RC, Rudack T, Yu H, Wu Z, Schulten K (2015) Molecular dynamics simulations of large macromolecular complexes. Curr Opin Struct Biol 31:64–74CrossRefGoogle Scholar
  36. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612CrossRefGoogle Scholar
  37. 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
  38. Putnam CD, Hammel M, Hura GL, Tainer JA (2007) X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution. Q Rev Biophys 40:191–285CrossRefGoogle Scholar
  39. Rambo RP, Tainer JA (2013) Accurate assessment of mass, models and resolution by small-angle scattering. Nature 496:477–481CrossRefGoogle Scholar
  40. Saunders MG, Voth GA (2013) Coarse-graining methods for computational biology. Annu Rev Biophys 42:73–93CrossRefGoogle Scholar
  41. Schröder GF, Brunger AT, Levitt M (2007) Combining efficient conformational sampling with a deformable elastic network model facilitates structure refinement at low resolution. Structure 15:1630–1641CrossRefGoogle Scholar
  42. Singharoy A, Teo I, McGreevy R, Stone JE, Zhao J, Schulten K (2016) Molecular dynamics-based refinement and validation for sub-5 Å cryo-electron microscopy maps. Elife 5:e16105CrossRefGoogle Scholar
  43. Suhre K, Sanejouand Y-H (2004) ElNemo: a normal mode web server for protein movement analysis and the generation of templates for molecular replacement. Nucleic Acids Res 32:W610–W614CrossRefGoogle Scholar
  44. Suhre K, Navaza J, Sanejouand YH (2006) NORMA: a tool for flexible fitting of high-resolution protein structures into low-resolution electron-microscopy-derived density maps. Acta Crystallogr D Biol Crystallogr 62:1098–1100CrossRefGoogle Scholar
  45. Svergun D, Barberato C, Koch MHJ (1995) CRYSOL -- a Program to Evaluate X-ray Solution Scattering of Biological Macromolecules from Atomic Coordinates. J Appl Crystallogr 28:768–773CrossRefGoogle Scholar
  46. Takada S, Kanada R, Tan C, Terakawa T, Li W, Kenzaki H (2015) Modeling Structural Dynamics of Biomolecular Complexes by Coarse-Grained Molecular Simulations. Acc Chem Res 48:3026–3035CrossRefGoogle Scholar
  47. Tama F, Sanejouand YH (2001) Conformational change of proteins arising from normal mode calculations. Protein Eng 14:1–6CrossRefGoogle Scholar
  48. Tama F, Gadea FX, Marques O, Sanejouand YH (2000) Building-block approach for determining low-frequency normal modes of macromolecules. Proteins 41:1–7CrossRefGoogle Scholar
  49. Tama F, Wriggers W, Brooks CL III (2002) Exploring global distortions of biological macromolecules and assemblies from low-resolution structural information and elastic network theory. J Mol Biol 321:297–305CrossRefGoogle Scholar
  50. Tama F, Valle M, Frank J, Brooks CL III (2003) Dynamic reorganization of the functionally active ribosome explored by normal mode analysis and cryo-electron microscopy. Proc Natl Acad Sci USA 100:9319–9323CrossRefGoogle Scholar
  51. Tama F, Miyashita O, Brooks CL (2004) Flexible multi-scale fitting of atomic structures into low-resolution electron density maps with elastic network normal mode analysis. J Mol Biol 337:985–999CrossRefGoogle Scholar
  52. Tan RK-Z, Devkota B, Harvey SC (2008) YUP.SCX: coaxing atomic models into medium resolution electron density maps. J Struct Biol 163:163–174CrossRefGoogle Scholar
  53. Tirion MM (1996) Large amplitude elastic motions in proteins from a single- parameter, atomic analysis. Phys Rev Lett 77:1905–1908CrossRefGoogle Scholar
  54. Trabuco LG, Villa E, Mitra K, Frank J, Schulten K (2008) Flexible fitting of atomic structures into electron microscopy maps using molecular dynamics. Structure 16:673–683CrossRefGoogle Scholar
  55. Tria G, Mertens HD, Kachala M, Svergun DI (2015) Advanced ensemble modelling of flexible macromolecules using X-ray solution scattering. IUCrJ 2:207–217CrossRefGoogle Scholar
  56. Unverdorben P, Beck F, Śledź P, Schweitzer A, Pfeifer G, Plitzko JM, Baumeister W, Förster F (2014) Deep classification of a large cryo-EM dataset defines the conformational landscape of the 26S proteasome. Proc Natl Acad Sci U S A 111:5544–5549CrossRefGoogle Scholar
  57. Vashisth H, Skiniotis G, Brooks CL (2012) Using enhanced sampling and structural restraints to refine atomic structures into low-resolution electron microscopy maps. Structure 20:1453–1462CrossRefGoogle Scholar
  58. Whitford PC, Noel JK, Gosavi S, Schug A, Sanbonmatsu KY, Onuchic JN (2009) An all-atom structure-based potential for proteins: bridging minimal models with all-atom empirical forcefields. Proteins 75:430–441CrossRefGoogle Scholar
  59. Whitford PC, Ahmed A, Yu Y, Hennelly SP, Tama F, Spahn CMT, Onuchic JN, Sanbonmatsu KY (2011) Excited states of ribosome translocation revealed through integrative molecular modeling. Proc Natl Acad Sci U S A 108:18943–18948CrossRefGoogle Scholar
  60. Wu X, Subramaniam S, Case DA, Wu KW, Brooks BR (2013) Targeted conformational search with map-restrained self-guided Langevin dynamics: application to flexible fitting into electron microscopic density maps. J Struct Biol 183:429–440CrossRefGoogle Scholar
  61. Xu X, Yan C, Wohlhueter R, Ivanov I (2015) Integrative Modeling of Macromolecular Assemblies from Low to Near-Atomic Resolution. Comput Struct Biotechnol J 13:492–503CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.RIKEN R-CCSKobeJapan
  2. 2.Department of Physics and ITbMNagoya UniversityNagoyaJapan

Personalised recommendations