Biophysical Reviews

, Volume 10, Issue 2, pp 605–615 | Cite as

Multiscale molecular dynamics simulations of rotary motor proteins

  • Toru Ekimoto
  • Mitsunori Ikeguchi


Protein functions require specific structures frequently coupled with conformational changes. The scale of the structural dynamics of proteins spans from the atomic to the molecular level. Theoretically, all-atom molecular dynamics (MD) simulation is a powerful tool to investigate protein dynamics because the MD simulation is capable of capturing conformational changes obeying the intrinsically structural features. However, to study long-timescale dynamics, efficient sampling techniques and coarse-grained (CG) approaches coupled with all-atom MD simulations, termed multiscale MD simulations, are required to overcome the timescale limitation in all-atom MD simulations. Here, we review two examples of rotary motor proteins examined using free energy landscape (FEL) analysis and CG-MD simulations. In the FEL analysis, FEL is calculated as a function of reaction coordinates, and the long-timescale dynamics corresponding to conformational changes is described as transitions on the FEL surface. Another approach is the utilization of the CG model, in which the CG parameters are tuned using the fluctuation matching methodology with all-atom MD simulations. The long-timespan dynamics is then elucidated straightforwardly by using CG-MD simulations.


Molecular dynamics simulation Free energy calculation Coarse-grained molecular dynamics simulation F1-ATPase V1-ATPase 



This work was financially supported by Innovative Drug Discovery Infrastructure through Functional Control of Biomolecular Systems, Priority Issue 1 in Post-K Supercomputer Development from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to M.I. (Project ID: hp150269, hp160223, and hp170255); by Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from Japan Agency for Medical Research and Development (AMED) to M.I.; and by RIKEN Dynamic Structural Biology Project to M.I. We further thank collaborators Dr. Yuko Ito (AIST), Dr. Tomotaka Oroguchi (Keio University), Dr. Takashi Yoshidome (Tohoku University), Prof. Nobuyuki Matubayasi (Osaka Univeristy), Prof. Masahiro Kinoshita (Kyoto University), Dr. Yuta Isaka (FBRI), Dr. Yuichi Kokabu (MKI), Prof. Ichiro Yamato (Tokyo University of Science), and Prof. Takeshi Murata (Chiba University).

Compliance with ethical standards

Conflicts of interest

T. Ekimoto declares that he has no conflict of interest. M. Ikeguchi declare that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Abraham MJ, Murtola T, Schulz R, Pall S, Smith JC, Hess B, Lindahl E (2015) GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1-2:19–25. CrossRefGoogle Scholar
  2. Adachi K, Oiwa K, Nishizaka T, Furuike S, Noji H, Yoshida M, Kinoshita K Jr (2007) Coupling of rotation and catalysis in F1-ATPase revealed by single-molecule imaging and manipulation. Cell 130:309-321.
  3. Arai S, Saijo S, Suzuki K, Mizutani K et al (2013) Rotation mechanism of Enterococcus hirae V1-ATPase based on asymmetric crystal structures. Nature 493:703–707CrossRefPubMedGoogle Scholar
  4. Arora K, Brooks CL III (2007) Large-scale allosteric conformational transitions of adenylate kinase appear to involve a population-shift mechanism. Proc Natl Acad Sci USA 104:18496–18501. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Arora K, Brooks CL III (2009) Functionally important conformations of the Met20 loop in dihydrofolate reductase are populated by rapid thermal fluctuations. J Am Chem Soc 131:5642–5647. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Baba M, Iwamoto K, Iino R, Ueno H, Hara M, Nakanishi A, Kishikawa JI, Noji H, Yokoyama K (2016) Rotation of artificial rotor axles in rotary molecular motors. Proc Natl Acad Sci USA 112:11214–11219. CrossRefGoogle Scholar
  7. Beauchamp KA, Lin YS, Das R, Pande VS (2012) Are protein force fields getting better? A systematic benchmark on 524 diverse NMR measurements. J Chem Theory Comput 8:1409–1414. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Case DA, Cerutti DS, Cheatham TE III et al (2017) AMBER 2017. University of California, San FranciscoGoogle Scholar
  9. Chodera JD, Noe F (2014) Markov state models of biomolecular conformational dynamics. Curr Opin Struct Biol 25:135–144. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chu JW, Trout BL, Brooks BR (2003) A super-linear minimization scheme for the nudged elastic band method. J Chem Phys 119:12708–12717. CrossRefGoogle Scholar
  11. Dror RO, Dirks RM, Grossman JP, Xu H, Shaw DE (2012) Biomolecular simulation: a computational microscope for molecular biology. Annu Rev Biophys 41:429–452. CrossRefPubMedGoogle Scholar
  12. Furuike S, Hossain MD, Maki Y, Adachi K, Suzuki T, Kohori A, Itoh H, Yoshida M, Kinoshita K Jr (2008) Axle-less F1-ATPase rotates in the correct direction. Science 319:955-958. doi:
  13. Goh BC, Hadden JA, Bernardi RC, Singharoy A, McGreevy R, Rudack T, Cassidy CK, Schulten K (2016) Computational methodologies for real-space structural refinement of large macromolecular complexes. Annu Rev Biophys 45:253–278. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Hamelberg D, Mongan J, McCammon JA (2004) Accelerated molecular dynamics: a promising and efficient simulation method for biomolecules. J Chem Phys 120:11919. CrossRefPubMedGoogle Scholar
  15. Hayashi S, Ueno H, Shikh AR, Umemura M, Kamiya M, Ito Y, Ikeguchi M, Komoriya Y, Iino R, Noji H (2012) Molecular mechanism of ATP hydrolysis in F1-ATPase revealed by molecular simulations and single-molecule observations. J Am Chem Soc 134:8447–8454. CrossRefPubMedGoogle Scholar
  16. Iino R, Ueno H, Minagawa Y, Suzuki K, Murata T (2015) Rotational mechanism of Enterococcus hirae V1-ATPase by crystal—structure and single-molecule analysis. Curr Opin Struct Biol 31:49–56. CrossRefPubMedGoogle Scholar
  17. Ikeguchi M, Ueno J, Sato M, Kidera A (2005) Protein structural change upon ligand binding: linear response theory. Phys Rev Lett 94:078102. CrossRefPubMedGoogle Scholar
  18. Imamura H, Takeda M, Funamoto S, Shimabukuro K, Yoshida M, Yokoyama K (2005) Rotation scheme of V1-motor is different from that of F1-motor. Proc Natl Acad Sci USA 102:17929–17933. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Isaka Y, Ekimoto T, Kokabu Y, Yamato I, Murata T, Ikeguchi M (2017) Rotation mechanism of molecular motor V1-ATpase studied by multiscale molecular dynamics simulation. Biophys J 112:911–920. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Ito Y, Ikeguchi M (2010a) Molecular dynamics simulations of the isolated β subunit of F1-ATPase. Chem Phys Lett 490:80–83. CrossRefGoogle Scholar
  21. Ito Y, Ikeguchi M (2010b) Structural fluctuation and concerted motions in F1-ATPase: a molecular dynamics study. J Comput Chem 31:2175–2185. CrossRefPubMedGoogle Scholar
  22. Ito Y, Ikeguchi M (2014) Molecular dynamics simulations of F1-ATPase. Adv Exp Med Biol 805:411–440. CrossRefPubMedGoogle Scholar
  23. Ito Y, Ikeguchi M (2015) Mechanism of the αβ conformational change in F1-ATPase after ATP hydrolysis: free-energy simulations. Biophys J 108:85–97. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Ito Y, Oroguchi T, Ikeguchi M (2011) Mechanism of the conformational change of the F1-ATPase β subunit revealed by free energy simulations. J Am Chem Soc 133:3372–3380. CrossRefPubMedGoogle Scholar
  25. Ito Y, Yoshidome T, Matuyasi N, Kinoshita M, Ikeguchi M (2013) Molecular dynamics simulations of yeast F1-ATPase before and after 16° rotation of the γ subunit. J Phys Chem B 117:3298–3307. CrossRefPubMedGoogle Scholar
  26. Jonsson H, Mills G, Jacobsen KW (1998) Nudged elastic band method for finding minimum energy paths of transitions. In: Berne BJ, Cicotti G, Coker DF (eds) Classical and quantum dynamics in condensed phase simulations. World Scientific, Singapore, pp 385–404CrossRefGoogle Scholar
  27. Kabaleeswaran V, Puri N, Walker JE, Leslie AGW, Mueller DM (2006) Novel features of the rotary catalytic mechanism revealed in the structure of yeast F1-ATPase. EMBO J 25:5433–5442. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kenzaki H, Koga N, Hori N, Kanada R, Li W, Okazaki K, Yao XQ, Takada S (2011) CafeMol: a coarse-grained biomolecular simulator for simulating proteins at work. J Chem Theory Comput 7:1979–1989. CrossRefPubMedGoogle Scholar
  29. Kobayashi C, Jung J, Matunaga Y, Mori T, Ando T, Tamura K, Kamiya M, Sugita Y (2017) GENESIS 1.1: a hybrid-parallel molecular dynamics simulator with enhanced sampling algorithms on multiple computational platforms. J Comput Chem 38:2193–2206. CrossRefPubMedGoogle Scholar
  30. 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 13:1011–1021. CrossRefGoogle Scholar
  31. Lane TJ, Shukla D, Beauchamp KA, Pande VS (2013) To milliseconds and beyond: challenges in the simulation of protein folding. Curr Opin Struct Biol 23:58–65. CrossRefPubMedGoogle Scholar
  32. Li W, Wolynes PG, Takada S (2011) Fustration, specific sequence dependence, and nonlinearity in large-amplitude fluctuations of allosteric proteins. Proc Natl Acad Sci USA 108:3504–3509. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lindorff-Larsen K, Maragakis P, Piana S, Eastwood MP, Dror RO, Shaw DE (2012) Systematic validation of protein force fields against experimental data. PLoS One 7:e32131. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Masaike T, Koyama-Horibe F, Oiwa K, Yoshida M, Nishizaka T (2008) Cooperative three-step motions in catalytic subunits of F1-ATpase correlate with 80° and 40° substep rotations. Nat Struct Mol Biol 15:1326–1333. CrossRefPubMedGoogle Scholar
  35. Ohmura I, Morimoto G, Ohno Y, Hasegawa A, Taiji M (2014) MDGRAPE-4: a special-purpose computer system for molecular dynamics simulations. Philos Trans A Math Phys Eng Sci 372:20130387. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Okazaki K, Hummer G (2013) Phosphate release coupled to rotary motion of F1-ATPase. Proc Natl Acad Sci USA 110:16468–16473. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Okazaki K, Koga N, Takada S, Onuchic JN, Wolynes PG (2006) Multiple-basin energy landscapes for large-amplitude conformational motions of proteins: structure-based molecular dynamics simulations. Proc Natl Acad Sci USA 103:11844–11849. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Okazaki K, Takada S (2008) Dynamic energy landscape view of coupled binding and protein conformational change: induced-fit versus population-shift mechanisms. Proc Natl Acad Sci USA 105:11182–11187. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Okuno D, Fujisawa R, Iino R, Hirono-Hara Y, Imamura H, Noji H (2008) Correlation between the conformational states of F1-ATPase as determined from its crystal structure and single-molecule rotation. Proc Natl Acad Sci USA 105:20722–20727. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Okuno D, Iino R, Noji H (2011) Rotation and structure of FoF1-ATP synthase. J Biochem 149(6):655–664. CrossRefPubMedGoogle Scholar
  41. 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 26:1781–1802. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Piana S, Laio A (2007) A bias-exchange approach to protein folding. J Phys Chem B 111:4553–4559. CrossRefPubMedGoogle Scholar
  43. Rauscher S, Gapsys V, Gajda MJ, Zweckstetter M, de Groot BL, Grumbmüller (2015) Structural ensembles of intrinsically disordered proteins depend strongly on force field: a comparison to experiment. J Chem Theory Comput 11:5513–5524. CrossRefPubMedGoogle Scholar
  44. Roth R, Harano Y, Kinoshita M (2006) Morphometric approach to the solvation free energy of complex molecules. Phys Rev Lett 97:078101. CrossRefPubMedGoogle Scholar
  45. Saunders MG, Voth GA (2013) Coarse-graining methods for computational biology. Annu Rev Biophys 42:73–93. CrossRefPubMedGoogle Scholar
  46. Shaw DE, Deneroff MM, Dror RO, Kuskin JS, Larson RH, Salmon JK, Young C, Batson B, Bowers KJ, Chao JC (2008) Anton, a special-purpose machine for molecular dynamics simulation. Commun ACM 51:91–97. CrossRefGoogle Scholar
  47. Shimabukuro K, Yasuda R, Muneyuki E, Hara KY, Kinoshita K Jr, Yoshida M (2003) Catalysis and rotation of F1 motor: cleavage of ATP at the catalytic site occurs in 1 ms before 40° substep rotation. Proc Natl Acad Sci USA 100:14731–14736. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Singharoy A, Chipot C, Moradi M, Schulten K (2017) Chemomechanic coupling in hexametic protein–protein interfaces harness energy within V-type ATPases. J Am Chem Soc 139:293–310. CrossRefPubMedGoogle Scholar
  49. Stewart AG, Laming EM, Stobti M, Stoch D (2014) Rotary ATPases –dynami molecular machines. Curr Opin Struct Biol 25:40–48. CrossRefPubMedGoogle Scholar
  50. Sugita Y, Okamoto Y (1999) Replica-exchange molecular dynamics method for protein folding. Chem Phys Lett 314:141–151. CrossRefGoogle Scholar
  51. Suzuki K, Mizutani K, Maruyama S, Shimono K et al (2016) Crystal structures of the ATP-binding and ADP-release dwells of the V1 rotary motor. Nat Commun 7:13235–13244. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Torrie GM, Valleau JP (1974) Monte Carlo free energy estimates using non-Boltzmann sampling: application to the sub-critical Lennard-Jones fluid. Chem Phys Lett 28:578–581. CrossRefGoogle Scholar
  53. Watanabe R, Iino R, Noji H (2010) Phosphate release in F1-ATPase catalytic cycle follows ADP release. Nat Chem Biol 6:814–820. CrossRefPubMedGoogle Scholar
  54. Watanabe R, Noji H (2013) Chemomechanical coupling mechanism of F1-ATPase: catalysis and torque generation. FEBS Lett 587:1030–1035. CrossRefPubMedGoogle Scholar
  55. Weinan E, Vanden-Eijnden E (2010) Transition-path theory and path-finding algorithms for the study of rare events. Annu Rev Phys Chem 61:391–420. CrossRefGoogle Scholar
  56. Yao XQ, Kenzaki H, Murakami S, Takada S (2010) Drug export and allosteric coupling in a multidrug transporter revealed by molecular simulations. Nat Commun 1:117. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Yasuda R, Noji H, Kinoshita K Jr, Yoshida M (1998) F1-ATpase is a highly efficient motor that rotates with discrete 120-degree steps. Cell 93:1117–1124. CrossRefPubMedGoogle Scholar
  58. Yasuda R, Noji H, Yoshida M, Kinoshita K Jr, Itoh H (2010) Resolution of distinct rotational substeps by submillisecond kinetic analysis of F1-ATPase. Nature 410:898–904. CrossRefGoogle Scholar
  59. Yoshidome T, Ito Y, Ikeguchi M, Kinoshita M (2011) Rotation mechanism of F1-ATPase: crucial importance of the water entropy effect. J Am Chem Soc 133:4030–4039. CrossRefPubMedGoogle Scholar
  60. Yoshidome T, Ito Y, Matubayasi N, Ikeguchi M, Kinoshita M (2012) Structural characteristics of yeast F1-ATPase before and after 16-degree rotation of the γ subunit: theoretical analysis focused on the water-entropy effect. J Chem Phys 137:035102. CrossRefPubMedGoogle Scholar
  61. Zuckerman DM, Chong LT (2017) Weighted ensemble simulation: review of methodology, applications, and software. Annu Rev Biophys 46:43–57. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Graduate School of Medical Life ScienceYokohama City UniversityYokohamaJapan

Personalised recommendations