Abstract

Hybrid methods that combine quantum mechanics (QM) and molecular mechanics (MM) can be applied to studies of reaction mechanisms in locations ranging from active sites of small enzymes to multiple sites in large bioenergetic complexes. By combining the widely used molecular dynamics and visualization programs NAMD and VMD with the quantum chemistry packages ORCA and MOPAC, we created an integrated, comprehensive, customizable, and easy-to-use suite (http://www.ks.uiuc.edu/Research/qmmm). Through the QwikMD interface, setup, execution, visualization, and analysis are streamlined for all levels of expertise.

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Acknowledgements

The authors thank M.F. Herbst, C. Chipot, and G. Fiorin for helpful discussions. This work was supported by the National Science Foundation (NSF) (grants MCB-1616590, MCB-1244570, and PHY1430124 to Z.L.-S.), the US National Institutes of Health (NIH) (grant P41-GM104601 to Z.L.-S.), the Keck Foundation (grant 206231 to M.C.R.M. and Z.L.-S.), the Alexander von Humboldt Foundation (Feodor Lynen Postdoctoral Fellowship to T.R.), the Brazilian Coordination for Improvement of Higher Educational Personnel (CAPES; fellowship to J.D.C.M.; grant AUXPE1375/2014 to G.B.R.), and the Brazilian National Council for Scientific and Technological Development (CNPq 305271/2013-0 to G.B.R.). F.N. and C.R. acknowledge support for the development of ORCA by the Max Planck society (MPG) and the Germans Science Foundation (DFG). This research made use of Blue Waters sustained-petascale computing, which is supported by the state of Illinois and the NSF (OCI-0725070 and ACI-1238993). This work is part of the Petascale Computational Resource (PRAC) grant, which is supported by the NSF (ACI-1713784).

Author information

Author notes

    • Klaus Schulten

    Deceased.

    • Marcelo C R Melo
    •  & Rafael C Bernardi

    These authors contributed equally to this work.

Affiliations

  1. NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana–Champaign, Urbana, Illinois, USA.

    • Marcelo C R Melo
    • , Rafael C Bernardi
    • , Till Rudack
    • , James C Phillips
    • , João V Ribeiro
    • , John E Stone
    • , Klaus Schulten
    •  & Zaida Luthey-Schulten
  2. Center for Biophysics and Computational Biology, University of Illinois at Urbana–Champaign, Urbana, Illinois, USA.

    • Marcelo C R Melo
    •  & Zaida Luthey-Schulten
  3. Department of Biophysics, Ruhr-University Bochum, Bochum, Germany.

    • Till Rudack
  4. Biochemistry Center, Heidelberg University, Heidelberg, Germany.

    • Maximilian Scheurer
  5. Interdisciplinary Center for Scientific Computing, Heidelberg, Germany.

    • Maximilian Scheurer
  6. FAccTs GmbH, Köln, Germany.

    • Christoph Riplinger
  7. Center for Informatics, Federal University of Paraíba, João Pessoa, Brazil.

    • Julio D C Maia
  8. Department of Chemistry, Federal University of Paraíba, João Pessoa, Brazil.

    • Gerd B Rocha
  9. Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany.

    • Frank Neese
  10. Department of Physics, University of Illinois at Urbana–Champaign, Urbana, Illinois, USA.

    • Klaus Schulten
    •  & Zaida Luthey-Schulten
  11. Department of Chemistry, University of Illinois at Urbana–Champaign, Urbana, Illinois, USA.

    • Zaida Luthey-Schulten

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Contributions

M.C.R.M., R.C.B., T.R., K.S., and Z.L.-S. conceived the project. M.C.R.M. implemented the QM–MM interface. R.C.B., T.R., M.C.R.M., G.B.R., and K.S. discussed QM–MM features. J.D.C.M., G.B.R., C.R., and F.N. provided guidance on the development of the QM–MM interface. J.C.P. assisted in adapting NAMD. M.C.R.M. and M.S. prepared Python scripts for the interfaces of selected QM software packages. R.C.B. and M.C.R.M. performed all NAMD tests and simulations. J.D.C.M. and G.B.R. performed Amber calculations. R.C.B. and M.C.R.M. performed all free-energy calculations and analysis. M.S. and J.E.S. implemented the orbital visualization in VMD. J.V.R. and J.E.S. implemented the QM–MM graphical interface in QwikMD. R.C.B., M.C.R.M., T.R., M.S., G.B.R., F.N., and Z.L.-S. wrote and edited the manuscript. K.S. and Z.L.-S. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Zaida Luthey-Schulten.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–15, Supplementary Tables 1–6 and Supplementary Note

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    Life Sciences Reporting Summary

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Videos

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    QM–MM suite investigates the mechanism that sets up the genetic code

    NAMD's QM–MM interface was used to investigate the tRNA synthetase GluRS complex with its cognate tRNA and adenylate. Independent QM regions probed the two ends of an allosteric pathway that connects the anti-codon binding region to the active site, and network analysis was used to define the communication pathway, as well as highly correlated atom communities within the QM regions and across the QM–MM barrier. The reaction was studied with a combination of steered MD, string method and eABF, and the most likely mechanism was rendered using new VMD features, along with atomic orbitals calculated using NAMD/ORCA.