PmHMGR is an enzyme involved in the mevalonate pathway and catalyzes three different reactions in the active site: a hydride transfer, a base-catalyzed decomposition, and then a second hydride transfer. The reactions are dependent on the cofactor, NADH, and require a cofactor exchange after the first hydride transfer. The mechanism also involves large domain changes that can be hard to capture experimentally. To characterize the transition states (TSs) of the reaction, this study employed the Quantum to Molecular Mechanics (Q2MM) method. This involves using a quantum reference structure from QM/MM to parameterize a system-specific transition state force field and optimizing the parameters until they accurately reproduce the QM data. This gives a force field that treats the entire system at a consistent level and allows for long timescale simulations of the transition state. Although the lifetime of a TS is on the sub-picosecond timescale, microsecond simulations are necessary to sample the conformational changes of the protein going from the ground state of the x-ray structure to the conformation at the transition state, providing a detailed picture of the transition state stabilization by the protein. In this presentation, the results of 3 µs of molecular dynamics simulations of transition state for the second hydride transfer in PmHMGR are reported. The behavior of the flap domain (residues 377-428) at the TS is of particular interest because of its high degree of flexibility compared to other domains of the protein as well as its involvement in the cofactor exchange.

Microsecond molecular dynamic simulations on the second hydride transfer transition state of Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl reductase using Q2MM

253rd National Meeting (2017)

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