Nuclear Quantum Effects in Quantum Mechanical/Molecular Mechanical Free Energy Simulations of Ribonucleotide Reductase

• DOI: 10.1021/jacs.4c13955
• Publication Date: 2024-11-20T21:49:04Z
• Authors: Mathew Chow; Clorice R. Reinhardt; Sharon Hammes-Sch...
• Keywords: Ribonucleotide reductase; Umbrella sampling

The enzyme ribonucleotide reductase plays a critical role in DNA synthesis and repair. Its mechanism requires long-range radical transfer through series of proton-coupled electron (PCET) steps. Nuclear quantum effects such as zero-point energy, proton delocalization, hydrogen tunneling are known to be important PCET. We present strategy for efficiently incorporating nuclear into multidimensional free energy surfaces real-time dynamical simulations condensed-phase systems enzymes. This is based on the nuclear–electronic orbital (NEO) method, which treats specified protons mechanically same level electrons. NEO density functional theory (NEO-DFT) combined with mechanical/molecular mechanical finite temperature string method umbrella sampling via simple reweighting procedure. Application this PCET between two tyrosines, Y731 Y730, illustrates that could either raise or lower barrier, leading range possible kinetic isotope effects. Real-time time-dependent DFT (RT-NEO-TDDFT) highlight dynamics. These approaches enable incorporation wide chemically biologically processes.