posted on 2020-02-28, 20:35authored byNicolás
O. Foglia, Sara E. Bari, Darío A. Estrin
A combination
of in silico methods was used to
extend the experimental description of the reductive nitrosylation
mechanism in ferric hemeproteins with the molecular details of the
role of surrounding amino acids. The computational strategy consisted
in the estimation of potential energy profiles for the transition
process associated with the interactions of the coordinated N(NO)
moiety with O(H2O) or O(OH–) as nucleophiles,
and with distal amino acids as proton acceptors or affecting the stability
of transition states. We inspected the reductive nitrosylation in
three representative hemeproteins -sperm whale metmyoglobin, α
subunit of human methemoglobin and nitrophorin 4 of Rhodnius prolixus. For each case, classical molecular
dynamics simulations were performed in order to obtain relevant reactive
conformations, and a potential energy profile for the reactive step
was obtained using adiabatic mapping or nudged elastic band approaches
at the QM/MM level. Specifically, we report the role of a charged
Arg45 of myoglobin in destabilizing the transition state when H2O acts as nucleophile, differently to the neutral Pro43 of
the hemoglobin subunit. The case of the nitrophorin is unique in that
the access of the required water molecules is scarce, thus, preventing
the reaction.