Elucidating the impact of S-adenosylmethionine and histamine binding on N-methyltransferase conformational dynamics: Insights from an in silico study

S-adenosylmethionine (SAM)-dependent histamine N-methyltransferase (HNMT) is a crucial enzyme involved in histamine methylation, playing an important role in the epigenetic modification of biology. It entails the addition of methyl groups to histamine molecules, thereby regulating gene expression, cellular signal transduction, and other biological processes. Therefore, gaining a profound understanding of the detailed mechanism underlying HNMT-mediated methylation reactions is instrumental in elucidating the role of histamine methylation in biology. This study employed molecular dynamics (MD) simulations to assess the mechanism of cooperative catalytic reaction between the substrate-binding domain (S domain) and the cofactor-binding domain (C domain) of HNMT. The results indicated that the interplay between the cofactor (SAM) and the C domain was mostly unaltered by substrate Histamine (HSM) binding. Nevertheless, SAM binding could induce conformational changes in the S domain, thus creating a favorable environment for substrate recognition and catalysis. Additionally, key amino acid residues that significantly contributed to substrate binding were identified based on molecular mechanics-generalized Born surface area (MM/GBSA) calculations. These findings could serve as a theoretical basis for the design of potential inhibitors and modulators targeting HNMT.