Combined QM/MM and Monte Carlo study for redox leveling in Mn and Fe superoxide dismutase

• Published in: Journal of biological inorganic chemistry Vol. 23; no. 2; pp. 285 - 293
• Main Authors: Amin, Muhamed, Mohamed, Zainab, El-Sayed, Mohamed, Samy, Asmaa, Sultan, Afnan, Bassuoni, Mahmoud, Alkordi, Mohamed H.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2018; Springer Nature B.V; Springer
• Subjects: Biochemistry; Biochemistry & Molecular Biology; Biomedical and Life Sciences; Chemistry; Crystal structure; Crystallography, X-Ray; Density Functional Theory; Inorganic chemistry; Iron; Life Sciences; Metals; Microbiology; Monte Carlo Method; Original Paper; Oxidation-Reduction; Protein Conformation; Superoxide dismutase; Superoxide Dismutase - chemistry; Water; Midpoint potential; Superoxide dismutase; QM/MM; DFT; Monte Carlo
• ISSN: 0949-8257; 1432-1327
• DOI: 10.1007/s00775-017-1530-8

Superoxide dismutases (SOD) are vital enzymes for disproportionation of superoxide molecules in mammals. Despite the high similarity between the Mn-SOD and Fe-SOD, they are inactive if the metals in the active sites are exchanged. Here, we use DFT, QM/MM and Monte Carlo sampling to optimize the crystal structure and to calculate the mid-point potential for the native and substituted Mn/Fe-SOD. The optimized DFT and QM/MM structures of the Mn-SOD show a major conformational change for the conserved TYR34 compared to the X-ray structure. These changes reduce the distance between TYR34 and Mn ion to 2.59 Å, which yields a lower reduction potential for the Mn. On contrary, there is no significant difference between optimized and crystal structures in the Fe-SOD. The calculated E m values starting from the DFT structures of the active sites show similar pattern, in good agreement with those observed experimentally. However, the calculated E m values starting with the QM/MM structures that include the whole protein are significantly higher due to the desolvation penalty. In addition, the p K a values for the water ligand in the reduced state Mn(II) and Fe(II) were calculated. The water p K a in Mn-SOD is higher than that in Fe-SOD by 3.5 pH units, which is similar to the shift measured experimentally. Finally, we investigated the role of HIS30 and the effect of its protonation state on the E m values.