Virus as a whole: meso- and macroscopic structure and dynamics at all atom resolution (CECAM-Lorentz Workshop)

Location : CECAM-HQ-EPFL, Lausanne, Switzerland
October 5, 2015 – October 9, 2015

State of the art computers can simulate liquid molecular systems several hundred million atoms in size (tens of nanometres across) using classical molecular dynamics (MD) methodology. Experimentally, modern x-ray crystallography can measure atomistic structure of complete parts of living cells with up to ~0.1A resolution (for example, human ribosome [1], photosystem complex [2], entire virus [3,4]).  These two facts together imply that it is now possible for the first time to model the structure of an entire virus at atomistic resolution.  Even though at the moment there are no viruses whose complete structures are known (with the nucleic acid inside), it is a feasible task if the latest experimental data from cryo electron microscopy is used.  However, simulating the dynamics of such systems over biologically interesting times is still impractical (up to 1µs simulation is reported [5]).

It has been recognised that water surrounding biomolecules (sometimes termed “biological” water) plays the major role in the dynamics of the biomolecule, so much as it should be considered as an integral part of the biomolecular system. The simulation of atomistic (explicit) water takes up to 90% of computing resources. Such modelling of viral processes over biologically relevant times (microseconds to milliseconds) is likely to remain a challenge for atom-resolved MD.  Currently the only possibility to increase the simulated times is to model water as continuum in regions where the atomistic nature of water molecules is not critical (for example, in the bulk far from the biomolecules), which implies larger space and time scales.  A fundamental problem is how to link the coarser continuum and finer atomistic representations.

A promising direction is the development of hybrid molecular dynamics-hydrodynamics approaches [6,7,8]. Such approaches consistently combine the atomistic and continuum representations at different parts of the simulated system.  This will allow modelling of the virus itself and water near it at the necessary atomistic level and, at the same time, continuum water further away.  The approaches also allow the simultaneous investigations of processes at space and time scale with orders of magnitude difference. This provides unique opportunities for studying biologically and medically crucial phenomena such as, for example, meso- and macroscopic transport of viruses carried by hydrodynamic flows in and between cells combined with the molecular specificities of their interactions at the microscale with the cell membrane and organelles.

The two main fields of molecular research will be brought together: 1) high performance molecular dynamics modelling of large biomolecular systems and 2) hybrid multiscale molecular dynamics-hydrodynamics modelling. Meetings in the two fields separately tend to focus on one aspect of the problem only. High performance large scale molecular simulation meetings usually attract biologists and biochemists interested in the biochemical aspects of the results. The methodological elements of such meetings typically concentrate on hardware developments and numerical techniques, leaving the fundamental physics of the methods of lower importance. The hybrid multiscale methods discussions often concern general physical and mathematical aspects of new approaches. For natural reasons, the applications are limited to small systems such as pure water or solutions of small molecules. We propose to combine the two approaches in a single meeting involving world leading experts from both sides. Computational biochemists will be able to appreciate the benefits of multiscale methods. Hybrid methods experts will benefit from the in depth knowledge of biomolecular systems and feasibility of their modelling.

More specifically, the following problems will be considered:

  • Reconstructing the structure of large biomolecular systems at all-atom resolution from lower resolution experimental data, such as cryo-electron microscopy densities.

  • Obtaining meso- and macroscopic properties, such as mechanical elasticity, diffusion and viscosity properties, thermal conductivity, of large biomolecular objects (whole organelles, viruses) from all-atom simulations.

  • Changing the number of degrees of freedom when coarse graining atomistic models from all-atom to mesoscale for simple liquids, solutions of small molecules, and large biomolecular systems.

  • Developing Langevin-like equations of motion for coarse grained models of large biomolecular systems, calculating the friction coefficients for these equations.

  • Consistently combining fine scale all-atom representation of the system with coarse grained representation of the environment and other parts of the biomolecular object.

  • Developing realistic models of molecular fluctuations when going downscale from macroscopic continuous hydrodynamics towards atomistic level of description, using Landau-Lifshitz Fluctuating Hydrodynamics approach as the basis.

  • Developing effective implementations of atomistic, continuous, and hybrid frameworks in high performance computation hardware, designing and building specialised accelerators for these algorithms.




[1] Ben-Shem A, Garreau de Loubresse N, Melnikov S, Jenner L, Yusupova G, Yusupov M., “The structure of the eukaryotic ribosome at 3.0 Å resolution.”, Science, 2011 Dec 16, 334(6062):1524-9, doi:10.1126/science.1212642

[2] Yasufumi Umena, Keisuke Kawakami, Jian-Ren Shen & Nobuo Kamiya, “Crystal structure of oxygen-evolving photosystem II at a resolution of 1.9 Å”, Nature 473, 55–60, (05 May 2011), doi:10.1038/nature09913

[3] Plevka P, Perera R, Cardosa J, Kuhn RJ, Rossmann MG., “Crystal structure of human enterovirus 71”, Science. 2012 Jun 8;336(6086):1274. doi: 10.1126/science.1218713

[4] Reza Khayat, Nicholas Brunn, Jeffrey A Speir, John M Hardham, Robert G Ankenbauer, Anette Schneemann, John E Johnson, “The 2.3-angstrom structure of porcine circovirus 2”, Journal of virology 85 (15), 7856-7862 (2011)

[5] Larsson DSD, Liljas L, van der Spoel D (2012) Virus Capsid Dissolution Studied by Microsecond Molecular Dynamics Simulations. PLoS Comput Biol 8(5): e1002502. doi:10.1371/journal.pcbi.1002502

[6] G. De Fabritiis, R. Delgado-Buscalioni, and P. V. Coveney, “Multiscale Modeling of Liquids with Molecular Specificity”, Phys. Rev. Lett. 97, 134501 (2006)

[7] A. Markesteijn, S. Karabasov, A. Scukins, D. Nerukh, V. Glotov, and V. Goloviznin, “Concurrent multiscale modelling of atomistic and hydrodynamic processes in liquids”, Phil. Trans. A, Phil. Trans. R. Soc. A (2014) 372, 20130379

[8] E. Pavlov, M. Taiji, A. Scukins, A. Markesteijn, S. Karabasov, and D. Nerukh, “Visualising and controlling the flows in biomolecular systems at and between multiple scales: from atoms to hydrodynamics at different locations in time and space”, Faraday Discussions, Vol. 169, (2014), p. 285-302


Jade Forwood (Charles Sturt University)
Kate Smith (Charles Sturt University)


Jan Henning Peters (Free University Berlin)


Cristian Micheletti (International School for Advanced Studies (SISSA), Trieste)


Yoshimichi Andoh (Nagoya University)
Teruhisa Komatsu (RIKEN Advanced Institute for Computational Science)
Makoto Taiji (RIKEN Advanced Institute for Computational Science)

The Netherlands

Mariska van Rosmalen (Vrije Universiteit Amsterdam)
Gijs Wuite (Vrije Universiteit Amsterdam)

Russian Federation

Ivan Korotkin (Institute for Nuclear Safety, Russia)
Elvira Tarasova (Immanuel Kant Baltic Federal University)


Daniel Luque Buzo (National Centre for Biotechnolgy, Madrid)
Pedro José de Pablo Gomez (Autonomous University of Madrid )
Rafael Delgado-Buscalioni (Autonomous University of Madrid )


Justin Flatt (University of Zurich)
Urs Greber (University of Zurich, Switzerland)
Petr Leiman (Swiss Federal Institute of Technology, Lausanne (EPFL))
Alexander Muratov (CECAM, EPFL)


Jhih-Wei Chu (National Chiao Tung University)


Michael Hagan (Brandeis University, Waltham)
Reza Khayat (The City College of New York)
Phoebe L. Stewart (Case Western Reserve University, Cleveland)
Nikolaos Voulgarakis (Washington State University, Pullman)
Adam Zlotnick (Indiana University, Bloomington)

Monday October 5th 2015 – Day 1
Registration (with coffee)

09:30 to 10:15 – Registration

10:15 to 10:30 – Welcome
Setting the meeting: 4 minutes slides + list of problems to discuss

10:30 to 12:15 – Welcome and Introduction

12:15 to 14:00 – Lunch
Dmitry Nerukh

14:00 to 14:45 – Dmitry Nerukh 
Virus as a whole: meso- and macroscopic structure and dynamics at all atom resolution
Yoshimichi Andoh

14:45 to 15:30 – Yoshimichi Andoh 
All-atom molecular dynamics simulation study of entire poliovirus empty capsids in solution
Coffee break

15:30 to 16:00 – Coffee Break
Reza Khayat

16:00 to 16:45 – Presentation
Summary of the day and plan for tomorrow

16:45 to 17:15 – General Discussion and Conclusion
Tuesday October 6th 2015 – Day 2
Makoto Taiji

09:30 to 10:15 – Makoto Taiji 
Special-purpose computers for Molecular Dynamics simulations
Coffee break

10:15 to 10:45 – Coffee Break
Anton Markesteijn

10:45 to 11:15 – Anton Markesteijn 
Computational Methods for Multi-Scale Problems and Fluctuating Hydrodynamics
Ivan Korotkin (lecture+demonstration)

11:15 to 12:15 – Ivan Korotkin 
Multiscale modelling of fluids: implementation of fluctuating hydrodynamics in GROMACS

12:15 to 14:00 – Lunch
Rafael Delgado-Buscalioni

14:00 to 14:45 – Rafael Delgado-Buscalioni 
Combining tools in multiscale modelling: coarse graining, adaptive resolution, open-MD and immersed boundary fluctuating hydrodynamics.
Pedro de Pablo

14:45 to 15:30 – Pedro José de Pablo Gomez 
Physical Virology with Atomic Force Microscopy and beyond
Fondation l’Hermitage visit

16:30 to 18:30 – Get together
Dinner at Chalet Suisse

19:00 to 22:00 – Social Dinner
Wednesday October 7th 2015 – Day 3
Urs Greber

09:30 to 10:15 – Urs Greber 
The virus assembly – disassembly paradox
Coffee break

10:15 to 10:45 – Coffee Break
Petr Leiman

10:45 to 11:15 – Petr Leiman 
Contractile injection systems in viruses and bacteria
Daniel Luque Buzo

11:15 to 11:45 – Daniel Luque Buzo 
Near-atomic structure of Penicillium chrysogenum virus by cryo-electron microscopy

12:15 to 14:00 – Lunch
Elvira Tarasova

14:00 to 14:45 – Elvira Tarasova 
Molecular Dynamics Simulation of PCV2 Virus in Water with Atomistic Resolution
Jhih-Wei Chu

14:45 to 15:30 – Presentation
Coffee break

15:30 to 16:00 – Coffee Break
Michael Hagan

16:00 to 16:45 – Michael Hagan 
Simulations of efficient and specific virus assembly around RNA
Summary of the day and plan for tomorrow

16:45 to 17:15 – General Discussion and Conclusion
Thursday October 8th 2015 – Day 4
Andrew Abi-Mansour

09:30 to 10:15 – Presentation
Coffee break

10:15 to 10:45 – Coffee Break
Phoebe L. Stewart

10:45 to 11:30 – Phoebe L. Stewart 
Modeling the Interaction of Viruses with Innate Immune System Peptides by CryoEM and MDFF
Nikolaos Voulgarakis

11:30 to 12:15 – Nikolaos Voulgarakis 
Hybrid Methodologies for Nanoscale Fluid-Solid Interaction

12:15 to 14:00 – Lunch
Justin Flatt

14:00 to 14:30 – Justin Flatt 
Revealing how Adenovirus Docks and Delivers at the Nuclear Pore Complex
Kate Smith

14:30 to 15:00 – Kate Smith 
Atomic Resolution Structural Determination of Nuclear Import Complexes of Viral Proteins
Mariska van Rosmalen

15:00 to 15:30 – Presentation
Coffee break

15:30 to 16:00 – Presentation
Gijs Wuite

16:00 to 16:45 – Presentation
Summary of the day and plan for tomorrow

16:45 to 17:15 – General Discussion and Conclusion
Friday October 9th 2015 – Day 5
Adam Zlotnik

09:30 to 10:15 – Adam Zlotnick 
When assembly doesn’t follow recommended mechanisms
Coffee break

10:15 to 10:45 – Coffee Break
Teruhisa Komatsu

10:45 to 11:15 – Teruhisa Komatsu 
A glimpse of turbulence from the molecular scale
Jade Forwood

11:15 to 11:45 – Jade Forwood 
Assembly of virus capsids

12:15 to 14:00 – Lunch
Jan Henning Peters

14:00 to 14:45 – Jan Henning Peters 
Adaptive Resolution Simulations of Polymer chains
Cristian Micheletti

14:45 to 15:30 – Cristian Micheletti 
Mechanical and assembly units of viral capsids identified via quasi-rigid domain decomposition
Coffee break

15:30 to 16:00 – Coffee Break
Writing the report

16:00 to 16:45 – Discussion-Conclusions

16:45 to 17:15 – Discussion-Conclusions