Disease-Associated Mutations Impact DNA Methyltransferase 1 Function through Dynamic Allosteric Effects and Solvent Exposure

Mutations in the DNA methyltransferase 1 (DNMT1) enzyme can lead to neurodegenerative diseases, including autosomal dominant cerebellar ataxia-deafness and neuropathy (ADCA-DN) and hereditary sensory and autonomic neuropathy type 1E (HSAN1E). The impact of these mutations on the structural dynamics of DNMT1 remains largely unknown. Here, we present an extensive molecular dynamics investigation of wild-type (WT) DNMT1 and its mutants associated with ADCA-DN (A554V, G589A, and V590F) and HSAN1E (D490E-P491Y and Y495C). The first group of mutants increases structural flexibility and disrupts the allosteric communication relative to WT DNMT1. These findings provide a molecular explanation for the reduced in vitro thermostability observed in these mutants. The second group has a similar impact on structural flexibility and allosteric communication and increases solvent exposure at mutant sites, offering a plausible structural explanation for the experimentally observed aberrant protein degradation and cleavage. Furthermore, all the investigated variants alter the most significant large-scale motions of the enzyme. This disruption of motion, together with decreased structural stability, may affect DNMT1's molecular recognition processes with its cellular partners. Overall, this study sheds light on the molecular mechanisms underlying ADCA-DN and HSAN1E, which could inform the development of therapies.