title: A molecular dynamics simulation study decodes the early stage of the disassembly process abolishing the human SAMHD1 function.
abstract: The human sterile alpha motif SAM and HD domain-containing protein 1 (SAMHD1) restricts in non-cycling cells type the infection of a large range of retroviruses including HIV-1, reducing the intracellular pool concentration of deoxynucleoside triphosphates (dNTPs) required for the reverse transcription of the viral genome. The enzyme is in equilibrium between different forms depending on bound cofactors and substrate. In this work, two SAMHD1 three-dimensional models have been investigated through classical molecular dynamics simulation, to define the role of cofactors and metal ions in the association of the tetrameric active form. A detailed analysis of the inter-subunit interactions, taking place at the level of helix 13, indicates that removal of metal ions and cofactors induces an asymmetric loosening of the monomer-monomer interface leading to the formation of a loose tetramer where the two dimeric interfaces are weakened in different way.
authors.affiliation: Department of Biology, Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cardamone
authors.affiliation: Department of Biology, Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Iacovelli
authors.affiliation: SCAI (Super Computing Applications and Innovations) CINECA, Via dei Tizii, 6, 00185, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Chillemi
authors.affiliation: Department of Biology, Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Falconi
authors.affiliation: Department of Biology, Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy. desideri@uniroma2.it.
authors.forename: Alessandro
authors.identifier: http://orcid.org/0000-0003-1541-4217
authors.initials: A
authors.lastname: Desideri
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D020134:Catalytic Domain; D016000:Cluster Analysis; D006801:Humans; D007477:Ions; D008670:Metals / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry*; D025341:Principal Component Analysis; D011487:Protein Conformation; D055503:Protein Multimerization; D000076106:SAM Domain and HD Domain-Containing Protein 1
chemical_list: D007477:Ions; D008670:Metals; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins
keywords: Allosteric site; Classical molecular dynamics simulation; Principal component analysis; SAMHD1; Salt bridges and hydrogen bonds; Tetramer-dimer equilibrium