(73h) Unraveling the Quantum Mechanical Catalytic Action of Methyltransferases with GPU-Accelerated Large-Scale Electronic Structure

Methyltransferases play key roles in biological processes, including epigenetic modifications, protein repair, natural product biosynthesis, and neurotransmitter regulation. Although methyl transfer is believed to occur with an S_N2 mechanism for S-adenosyl-L-methionine (SAM)-dependent class I methyltransfases, the role of the greater enzyme environment remains under debated. Electrostatics, charge transfer, dynamics, and C-H^...O hydrogen bonding have all been suggested to contribute to reactivity. Here, we employ GPU-accelerated electronic structure calculations to explore the quantum mechanical catalytic origin of methyltransferase. We performed large-scale QM/MM calculations (~500-1000 QM atoms) on four representative class I methyltransferases, including 2’-O-ribose (CMTr1), phosphoethanolamine (PfPMT), L-isoaspartyl (PIMT), and C3-6-carboxymethyl-5-methyl-4-hydroxy-2-pyridinol (HcgC) methyltransferases. We observe that favorable electrostatic interaction between the methyl donor SAM and the substrate is largely maintained from reactant to transition state region, which is resulted from charge transfer between the reacting molecule (SAM + substrate) and their greater protein environment. CHO(N) hydrogen bonds, albeit weak, were observed in all methyltransferases studied here. From reactant to transition state region, the hydrogen bonding interactions were found to be slightly enhanced in CMTr1, PfPMT, and HcgC, but diminished in PIMT. Our work demonstrates the promising utilization of GPU-accelerated quantum mechanical simulation to understand fundamental biochemical problems.