Abstract
Combining multi-level quantum mechanics theories and molecular mechanics with an explicit water model, we investigated the ring opening process of guanine damage by hydroxyl radical in aqueous solution. The detailed, atomic-level ring-opening mechanism along the reaction pathway was revealed in aqueous solution at the CCSD(T)/MM levels of theory. The potentials of mean force in aqueous solution were calculated at both the DFT/MM and CCSD(T)/MM levels of the theory. Our study found that the aqueous solution has a significant effect on this reaction in solution. In particular, by comparing the geometries of the stationary points between in gas phase and in aqueous solution, we found that the aqueous solution has a tremendous impact on the torsion angles much more than on the bond lengths and bending angles. Our calculated free-energy barrier height 31.6 kcal/mol at the CCSD(T)/MM level of theory agrees well with the one obtained based on gas-phase reaction profile and free energies of solvation. In addition, the reaction path in gas phase was also mapped using multi-level quantum mechanics theories, which shows a reaction barrier at 19.2 kcal/mol at the CCSD(T) level of theory, agreeing very well with a recent ab initio calculation result at 20.8 kcal/mol.
Highlights
We treated the solute 8-OHGrad as the QM region described using the multi CCSD(T), DFT and electrostatic potential (ESP)[53] levels of theory during different stages of calculation, and treated water solution as the classical MM region
Vqm represents the potential of QM region with the same expression as in the gas phase and Vmm is the molecular mechanical energy of the MM region
By employing multi-level quantum theories, including the ESP, DFT and CCSD(T), for the QM region, we started from the low level, a relatively inexpensive DFT/MM level of theory, shifted the calculation to the CCSD(T)/MM level of theory to achieve the more accurate PMF
Summary
Combining multi-level quantum mechanics theories and molecular mechanics with an explicit water model, we investigated the ring opening process of guanine damage by hydroxyl radical in aqueous solution. In this study, we want to investigate the ring opening process of hydroxyl radical attacking guanine in gas phase, and to investigate its reaction pathway in its real environment: aqueous solution. In this work, we combined multi-level quantum mechanics theories and molecular mechanics (ML-QM/MM)[43,44,45], to investigate the solvent effects on the guanine ring-opening mechanism under OH radical attack, to map an accurate potential of mean force (PMF) at the more accurate CCSD(T)/MM level of theory. The direct calculated PMF at the CCSD(T)/MM level of theory was verified by comparing with the PMF derived using the gas-phase potential minimum energy path and free energies of solvation
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