Accurate Quantum Mechanical/Molecular Mechanical Calculations of Reduction Potentials in Azurin Variants.

Understanding the regulation mechanism and molecular determinants of the reduction potential of metalloprotein is a major challenge. An ab initio quantum mechanical/molecular mechanical (QM/MM) method combining the minimum free energy path (MFEP) and fractional number of electron (FNE) approaches has been developed in our group to simulate the redox processes of large systems. The FNE scheme provides an efficient unique description for the redox process, while the MFEP method provides improved conformational sampling on complex environments such as protein in the QM/MM calculations. The reduction potentials of wild-type and seven mutants of azurin, a type 1 copper metalloprotein, were simulated with the QM/MM-MFEP+FNE approach in this paper. A range of 350 mV for the variations of the reduction potentials of these azurin proteins was reproduced faithfully with relative errors around 20 mV. The correlation between structural interactions and reduction potentials observed in simulations provides in-depth insight into the regulation of reduction potentials, which potentially can also be very useful to the engineering of metalloprotein-based electrocatalysts in artificial photosynthesis. The excellent accuracy and efficiency of the QM/MM-MFEP+FNE approach demonstrate the potential for simulations of many electron transfer processes in condensed phases and biochemical systems.