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Study of base pair mutations in proline-rich homeodomain (PRH)–DNA complexes using molecular dynamics

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Abstract

Proline-rich homeodomain (PRH) is a regulatory protein controlling transcription and gene expression processes by binding to the specific sequence of DNA, especially to the sequence 5′-TAATNN-3′. The impact of base pair mutations on the binding between the PRH protein and DNA is investigated using molecular dynamics and free energy simulations to identify DNA sequences that form stable complexes with PRH. Three 20-ns molecular dynamics simulations (PRH–TAATTG, PRH–TAATTA and PRH–TAATGG complexes) in explicit solvent water were performed to investigate three complexes structurally. Structural analysis shows that the native TAATTG sequence forms a complex that is more stable than complexes with base pair mutations. It is also observed that upon mutation, the number and occupancy of the direct and water-mediated hydrogen bonds decrease. Free energy calculations performed with the thermodynamic integration method predict relative binding free energies of 0.64 and 2 kcal/mol for GC to AT and TA to GC mutations, respectively, suggesting that among the three DNA sequences, the PRH–TAATTG complex is more stable than the two mutated complexes. In addition, it is demonstrated that the stability of the PRH–TAATTA complex is greater than that of the PRH–TAATGG complex.

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Acknowledgments

Computations were performed on the gpc supercomputer at the SciNet (Loken et al. 2010) HPC Consortium. SciNet is funded by: the Canada Foundation for Innovation under the auspices of Compute Canada; the Government of Ontario; Ontario Research Fund—Research Excellence; and the University of Toronto.

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Authors and Affiliations

  1. Department of Chemistry, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran

    Seifollah Jalili & Leila Karami

  2. Computational Physical Sciences Research Laboratory, Department of Nano-Science, Institute for Studies in Theoretical Physics and Mathematics (IPM), P.O. Box 19395-5531, Tehran, Iran

    Seifollah Jalili

  3. Chemical Physics Theory Group, Department of Chemistry, University of Toronto, 80 Saint George Street, Toronto, ON, M5S 3H6, Canada

    Jeremy Schofield

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  1. Seifollah Jalili
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Correspondence to Seifollah Jalili.

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Jalili, S., Karami, L. & Schofield, J. Study of base pair mutations in proline-rich homeodomain (PRH)–DNA complexes using molecular dynamics. Eur Biophys J 42, 427–440 (2013). https://doi.org/10.1007/s00249-013-0892-2

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  • DOI: https://doi.org/10.1007/s00249-013-0892-2

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