Predicting Binding Free Energies for DPS Protein-DNA Complexes and Crystals Using Molecular Dynamics




molecular dynamics, slow-growth thermodynamic integration method, DPS protein, DNA stabilization, DNA-DPS binding free energy


The interaction between deoxyribonucleic acid (DNA) and deoxyribonucleic acid-binding protein from starved cells (DPS) in bacterial cells leads to intracellular crystallization of the genetic material of bacteria, which contributes to the survival of bacteria under stress factors, including antibacterial agents. Molecular modeling can help explain the molecular mechanisms of DNA binding to this protein. In this paper, we report a supercomputer simulation of the molecular dynamics of several types DNA-DPS complexes and crystals ranging from DPS+DNA dimer to DNA in periodic crystal channels of Escherichia coli DPS protein using a coarse-grained Martini force field. By modeling DNA of 24 base pairs, comparable in size to the diameter of the DPS protein, we use the slow-growth thermodynamic integration method to find binding protein-DNA free energy and discuss the contribution of ions and the length of trajectories sufficient for this type of simulations. The results obtained are important for further research in the field of simulation of biological DNA-protein crystals and the study of the molecular mechanisms of DNA interaction with the DPS protein.


Almiron, M., Link, A.J., Furlong, D., Kolter, R.: A novel DNA-binding protein with regulatory and protective roles in starved escherichia coli. Genes & Development 6(12b), 2646–2654 (dec 1992).

Amemiya, H.M., Schroeder, J., Freddolino, P.L.: Nucleoid-associated proteins shape chromatin structure and transcriptional regulation across the bacterial kingdom. Transcription 12(4), 182–218 (aug 2021).

Antipov, S.S., Tutukina, M.N., Preobrazhenskaya, E.V., et al.: The nucleoid protein Dps binds genomic DNA of Escherichia coli in a non-random manner. PLOS ONE 12(8), e0182800 (aug 2017).

Bennett, C.H.: Efficient estimation of free energy differences from Monte Carlo data. Journal of Computational Physics 22(2), 245–268 (oct 1976).

Chiancone, E., Ceci, P.: The multifaceted capacity of dps proteins to combat bacterial stress conditions: Detoxification of iron and hydrogen peroxide and DNA binding. Biochimica et Biophysica Acta (BBA) - General Subjects 1800(8), 798–805 (aug 2010).

Dadinova, L.A., Chesnokov, Y.M., Kamyshinsky, R.A., et al.: Protective Dps-DNA cocrystallization in stressed cells: an in vitro structural study by small-angle X-ray scattering and cryo-electron tomography. FEBS Letters 593(12), 1360–1371 (2019).

Frenkiel-Krispin, D., Minsky, A.: Nucleoid organization and the maintenance of DNA integrity in E. coli, B. subtilis and D. radiodurans. Journal of Structural Biology 156(2), 311–319 (nov 2006).

Goga, N., Rzepiela, A.J., de Vries, A.H., et al.: Efficient algorithms for langevin and DPD dynamics. Journal of Chemical Theory and Computation 8(10), 3637–3649 (jun 2012).

Grant, R.A., Filman, D.J., Finkel, S.E., et al.: The crystal structure of Dps, a ferritin homolog that binds and protects DNA. Nature Structural Biology 5(4), 294–303 (apr 1998).

Hadley, K.R., McCabe, C.: Coarse-grained molecular models of water: a review. Molecular Simulation 38(8-9), 671–681 (jul 2012).

Hess, B., Kutzner, C., van der Spoel, D., Lindahl, E.: GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. Journal of Chemical Theory and Computation 4(3), 435–447 (feb 2008).

Huertas, J., Cojocaru, V.: Breaths, twists, and turns of atomistic nucleosomes. Journal of Molecular Biology 433(6), 166744 (mar 2021).

de Jong, D.H., Singh, G., Bennett, W.F.D., et al.: Improved Parameters for the Martini Coarse-Grained Protein Force Field. Journal of chemical theory and computation 9(1), 687–697 (2013).

Karas, V.O., Westerlaken, I., Meyer, A.S.: The DNA-binding protein from starved cells (dps) utilizes dual functions to defend cells against multiple stresses. Journal of Bacteriology 197(19), 3206–3215 (oct 2015).

Kovalenko, V., Popov, A., Santoni, G., et al.: Multi-crystal data collection using synchrotron radiation as exemplified with low-symmetry crystals of Dps. Acta Crystallographica Section F Structural Biology Communications 76(11), 568–576 (oct 2020).

Krupyanskii, Y.F., Loiko, N.G., Sinitsyn, D.O., et al.: Biocrystallization in bacterial and fungal cells and spores. Crystallography Reports 63(4), 594–599 (jul 2018).

Loiko, N., Danilova, Y., Moiseenko, A., et al.: Morphological peculiarities of the DNAprotein complexes in starved Escherichia coli cells. PLOS ONE 15(10), e0231562 (oct 2020).

Luijsterburg, M.S., White, M.F., van Driel, R., Dame, R.T.: The major architects of chromatin: Architectural proteins in bacteria, archaea and eukaryotes. Critical Reviews in Biochemistry and Molecular Biology 43(6), 393–418 (jan 2008).

Marrink, S.J., Risselada, H.J., Yefimov, S., et al.: The MARTINI force field: coarse grained model for biomolecular simulations. The Journal of Physical Chemistry B 111(27), 7812–7824 (2007).

Marrink, S.J., Tieleman, D.P.: Perspective on the Martini model. Chemical Society Reviews 42(16), 6801 (2013).

Martinez, J.L.: The role of natural environments in the evolution of resistance traits in pathogenic bacteria. Proceedings of the Royal Society B: Biological Sciences 276(1667), 2521–2530 (apr 2009).

Miller, J.L., Kollman, P.A.: Solvation free energies of the nucleic acid bases. The Journal of Physical Chemistry 100(20), 8587–8594 (jan 1996).

Minsky, A., Shimoni, E., Frenkiel-Krispin, D.: Stress, order and survival. Nature Reviews Molecular Cell Biology 3(1), 50–60 (jan 2002).

Mobley, D.L., Chodera, J.D., Dill, K.A.: On the use of orientational restraints and symmetry corrections in alchemical free energy calculations. The Journal of Chemical Physics 125(8), 084902 (aug 2006).

Mobley, D.L., Chodera, J.D., Dill, K.A.: Confine-and-release method: Obtaining correct binding free energies in the presence of protein conformational change. Journal of Chemical Theory and Computation 3(4), 1231–1235 (may 2007).

Moiseenko, A., Loiko, N., Tereshkina, K., et al.: Projection structures reveal the position of the DNA within DNA-Dps Co-crystals. Biochemical and Biophysical Research Communications 517(3), 463–469 (sep 2019).

Nair, S., Finkel, S.E.: Dps protects cells against multiple stresses during stationary phase. Journal of Bacteriology 186(13), 4192–4198 (jul 2004).

Parrinello, M., Rahman, A.: Polymorphic transitions in single crystals: A new molecular dynamics method. Journal of Applied Physics 52(12), 7182–7190 (dec 1981).

Periole, X., Cavalli, M., Marrink, S.J., Ceruso, M.A.: Combining an elastic network with a coarse-grained molecular force field: Structure, dynamics, and intermolecular recognition. Journal of chemical theory and computation 5(9), 2531–2543 (2013).

Pettersen, E.F., Goddard, T.D., Huang, C.C., et al.: UCSF Chimera–A visualization system for exploratory research and analysis. Journal of Computational Chemistry 25(13), 1605–1612 (2004).

Pham, T.T., Shirts, M.R.: Optimal pairwise and non-pairwise alchemical pathways for free energy calculations of molecular transformation in solution phase. The Journal of Chemical Physics 136(12), 124120 (mar 2012).

Shaytan, A.K., Armeev, G.A., Goncearenco, A., et al.: Coupling between histone conformations and DNA geometry in nucleosomes on a microsecond timescale: Atomistic insights into nucleosome functions. Journal of Molecular Biology 428(1), 221–237 (jan 2016).

Shen, B.A., Landick, R.: Transcription of bacterial chromatin. Journal of Molecular Biology 431(20), 4040–4066 (sep 2019).

Sinitsyn, D.O., Loiko, N.G., Gularyan, S.K., et al.: Biocrystallization of bacterial nucleoid under stress. Russian Journal of Physical Chemistry B 11(5), 833–838 (sep 2017).

Szatmári, D., Sárkány, P., Kocsis, B., et al.: Intracellular ion concentrations and cationdependent remodelling of bacterial MreB assemblies. Scientific Reports 10(1) (jul 2020).

Tereshkin, E.V., Tereshkina, K.B., Kovalenko, V.V., et al.: Structure of DPS protein complexes with DNA. Russian Journal of Physical Chemistry B 13(5), 769–777 (sep 2019).

Tereshkin, E.V., Tereshkina, K.B., Krupyanskii, Y.F.: Molecular dynamics of DNA-binding protein and its 2D-crystals. Journal of Physics: Conference Series 2056(1), 012016 (oct 2021).

Tereshkin, E., Tereshkina, K., Loiko, N., et al.: Interaction of deoxyribonucleic acid with deoxyribonucleic acid-binding protein from starved cells: cluster formation and crystal growing as a model of initial stages of nucleoid biocrystallization. Journal of Biomolecular Structure and Dynamics 37(10), 2600–2607 (nov 2018).

Tkachenko, A.G.: Stress responses of bacterial cells as mechanism of development of antibiotic tolerance (review). Applied Biochemistry and Microbiology 54(2), 108–127 (mar 2018).

Uusitalo, J.J., Ingólfsson, H.I., Akhshi, P., et al.: Martini coarse-grained force field: Extension to DNA. Journal of chemical theory and computation 11(8), 3932–3945 (2015).

Verma, S.C., Qian, Z., Adhya, S.L.: Architecture of the escherichia coli nucleoid. PLOS Genetics 15(12), e1008456 (dec 2019).

Wolf, S.G., Frenkiel, D., Arad, T., et al.: DNA protection by stress-induced biocrystallization. Nature 400(6739), 83–85 (jul 1999).




How to Cite

Tereshkin, E. V., Tereshkina, K. B., & Krupyanskii, Y. F. (2022). Predicting Binding Free Energies for DPS Protein-DNA Complexes and Crystals Using Molecular Dynamics. Supercomputing Frontiers and Innovations, 9(2), 33–45.