Understanding Mercury Transport and Transformation by Computational Simulations

Mercury is a global pollutant that can be transported over long distance and bio-amplified within food chains. It has been shown that anaerobic microorganisms can produce neurotoxin methylmercury from inorganic mercury. However, the mechanisms for Hg substrates uptake and bio-transformed mercury product export are still not clear. Also, once Hg substrates are inside the cells, the enzymatic mechanisms of mercury methylation are still unknown. In this dissertation, we focused on using computational approaches to understand how microorganisms uptake and export mercury complexes and the biotransformation mechanisms of inorganic mercury to methylmercury at the molecular level. Here, we first explored the catalytic mechanism of mercury methylation enzyme HgcA using a simplified model of methylcobalamin (the cofactor of HgcA). We found that the ligand substitution of the lower-axial side of methylcobalamin by the Cys residue from HgcA indeed facilitates methyl transfer. We then developed a consistent computational approach to investigate redox potential, pKas [pKitalic_as] and Co–ligand binding equilibrium constants for cobalamins. We used this approach to study the pH-dependent redox chemistry of aquacobalamin and yielded agreement with experimental values within 90 mV [millivolts] for reduction potentials and 1.0 log units both for pKas [pKitalic_as] and log Kon/off [Kitalic_on/off]. This study built the foundation to explore the redox requirements for another mercury methylation enzyme HgcB. Finally, we tested the possibility of passive permeation of Hg complexes through a model cytoplasmic membrane using molecular dynamics simulations. We concluded that small neutral Hg complexes in this study, i.e. CH3Hg– SCH3 and CH3S–Hg–SCH3, could permeate the model membrane without the facilitation of membrane proteins. We also investigated the kinetic aspect of the permeation processes and we predicted the permeability coefficients for the Hg-containing compounds are ~10-5 cm s-1 [centimeter per second]. Our studies here shed light on understanding the fundamental enzymatic mechanisms of mercury methylation, build the foundation for future study on the pH-dependent redox chemistry of metal-containing species, and established the future direction for studying the transport mechanisms of mercury complexes in microorganisms