Journal of Computer-Aided Molecular Design

, Volume 32, Issue 5, pp 623–632 | Cite as

Molecular dynamics characterization of the SAMHD1 Aicardi–Goutières Arg145Gln mutant: structural determinants for the impaired tetramerization

  • Francesca Cardamone
  • Mattia Falconi
  • Alessandro Desideri


Aicardi–Goutières syndrome, a rare genetic disorder characterized by calcification of basal ganglia, results in psychomotor delays and epilepsy states from the early months of children life. This disease is caused by mutations in seven different genes encoding proteins implicated in the metabolism of nucleic acids, including SAMHD1. Twenty SAMHD1 gene variants have been discovered and in this work, a structural characterization of the SAMHD1 Aicardi–Goutières Arg145Gln mutant is reported by classical molecular dynamics simulation. Four simulations have been carried out and compared. Two concerning the wild-type SAMHD1 form in presence and absence of cofactors, in order to explain the role of cofactors in the SAMHD1 assembly/disassembly process and, two concerning the Arg145Gln mutant, also in presence and absence of cofactors, in order to have an accurate comparison with the corresponding native forms. Results show the importance of native residue Arg145 in maintaining the tetramer, interacting with GTP cofactor inside allosteric sites. Replacement of arginine in glutamine gives rise to a loosening of GTP–protein interactions, when cofactors are present in allosteric sites, whilst in absence of cofactors, the occurrence of intra and inter-chain interactions is observed in the mutant, not seen in the native enzyme, making energetically unfavourable the tetramerization process.


Genetic disease Classical all-atomistic molecular dynamics simulation Allosteric site Salt bridge Hydrogen bond Oligomerization 



This work has been supported from the CINECA center ( due to the project IscraC award. The authors would like to acknowledge the HPC support assistance of the CINECA center and the MD group of Prof. Siewert Jan Marrink (University of Groningen, The Netherlands) for the hospitality and critical useful discussion.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10822_2018_115_MOESM1_ESM.docx (3.6 mb)
Supplementary material 1 (DOCX 3642 KB)


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biology, Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB)University of Rome Tor VergataRomeItaly

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