Understanding the R882H mutation effects of DNA methyltransferase DNMT3A: a combination of molecular dynamics simulations and QM/MM calculations.

ABSTRACT: DNA (cytosine-5)-methyltransferase 3A (DNMT3A), a key enzyme for de novo epigenetic methylation in human beings, was reported to undergo an R882H mutation in approximately 25% of M4/M5 subtype acute myeloid leukemia (AML) patients. In this work, a combination of classical molecular dynamics (MD) simulations and QM/MM calculation methods was utilized to reveal the molecular mechanism behind the activity attenuation caused by R882H mutation. We found that R882H mutation induces a "folded" conformation in the methyl donor S-adenosylmethionine (SAM) through different types of hydrogen bond formation at the terminal carbonyl oxygen atom and the hydroxyl O3' atom of the ribose ring on SAM, with Arg891 as a mediator. Energetically, both the pre-reaction state (PRS) and transition st

SUBMITTER: Liu L 

PROVIDER: S-EPMC9072302 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature