Homology modeling and molecular dynamics simulations of HgiDII methyltransferase in complex with DNA and S-adenosyl-methionine: Catalytic mechanism and interactions with DNA

M.HgiDII is a methyltransferase (MTase) from Herpetosiphon giganteus that recognizes the sequence GTCGAC. This enzyme belongs to a group of MTases that share a high degree of amino acid similarity, albeit none of them has been thoroughly characterized. To study the catalytic mechanism of M.HgiDII and its interactions with DNA, we performed molecular dynamics simulations with a homology model of M.HgiDII complexed with DNA and S-adenosyl-methionine. Our results indicate that M.HgiDII may not rely only on Glu119 to activate the cytosine ring, which is an early step in the catalysis of cytosine methylation; apparently, Arg160 and Arg162 may also participate in the activation by interacting with cytosine O2. Another residue from the catalytic site, Val118, also played a relevant role in the catalysis of M.HgiDII. Val118 interacted with the target cytosine and kept water molecules from accessing the region of the catalytic pocket where Cys79 interacts with cytosine, thus preventing water-mediated disruption of interactions in the catalytic site. Specific recognition of DNA was mediated mainly by amino acids of the target recognition domain, although some amino acids (loop 80–88) of the catalytic domain may also contribute to DNA recognition. These interactions involved direct contacts between M.HgiDII and DNA, as well as indirect contacts through water bridges. Additionally, analysis of sequence alignments with closely related MTases helped us to identify a motif in the TRD of M.HgiDII that may be relevant to specific DNA recognition.