Atomistic Simulation of NO Dioxygenation in Group I Truncated Hemoglobin

Abstract

NO dioxygenation, i.e., the oxidation of nitric oxide to nitrate by oxygen-bound truncated hemoglobin (trHbN) is studied using reactive molecular dynamics simulations. This reaction is an important step in a sequence of events in the overall NO detoxification reaction involving trHbN. The simulations ( approximately 160 ns in total) reveal that the reaction favors a pathway including (i) NO binding to oxy-trHbN, followed by (ii) rearrangement of peroxynitrite-trHbN to nitrato-trHbN, and finally (iii) nitrate dissociation from nitrato-trHbN. Overall, the reactions occur within tens of picoseconds and the crossing seam of the reactant and product are found to be broad. The more conventional pathway, where the peroxynitrite-trHbN complex undergoes peroxide cleavage to form free NO(2) and oxo-ferryl trHbN, is found to be too slow due to a considerable barrier involved in peroxide bond dissociation. The energetics of this step is consistent with earlier electronic structure calculations and make this pathway less likely. The role of Tyr33 and Gln58 in the NO dioxygenation has been investigated by studying the reaction in mutants of trHbN. The mutation study suggests that residues Tyr33 and Gln58 preorient the reactive ligands through a highly dynamical H-bonding network which facilitates the reaction. In particular, the Y33A mutation leads to a significant retardation in NO dioxygenation, in agreement with experiments which reveal a strong influence of the protein environment on the reaction rate.

Quantitative Atomistic Simulations of Reactive and Non-Reactive Processes

“…This is usually not a limitation for reactions in the condensed phase. [36,38] However, for gas-phase reactions, final state analysis becomes meaningless. [32,35] Multi-Surface-ARMD (MS-ARMD) is an energy-based switching method which yields energy-conserving trajectories.…”

“…[25][26][27] Alternatively, if empirical and fully-dimensional force fields of sufficient accuracy can be parametrized, they offer a viable means to exhaustively sample phase space from which meaningful rate parameters can be determined. [28][29][30][31][32][33] One of the methods developed by us is adiabatic reactive MD (ARMD). Two variants exist for this: a time-based [29,34] and an energy-based switching scheme.…”

“…In the simplest case, one force field describes the reactant and a second one the product state. [32,[36][37][38] However, additional physically meaningful states (e.g. intermediates) can be included in order to more completely describe the physical situation.…”

Mechanisms of Nitric Oxide Reactions Mediated by Biologically Relevant Metal Centers

“…Even at 100 K, the purported peroxynitrite intermediate Fe III (TPP)(OONO -) was not observable, so it was concluded that once this species is formed, it must decay very rapidly to the more stable nitrate complex Fe III (TPP)(NO 3 -). Notably, different computational approaches also disagree on the potential stability of that intermediate [172,173]. Superficially, the reaction of O 2 with nitrosyl myoglobin Mb(NO) (27) appears similar to that of NO with Mb(O 2 ).…”

Photodissociation Dynamics of ClCN at Different Wavelengths

“…Therefore, computer-assisted approaches have been developed to provide insight at an atomistic level. [31][32][33] Computational studies of dissociation processes have a long history. Due to the complexity of the problem, they initially focused on small molecules including H 2 O, ClCN, ICN, BrCN, and CH 3 I, and corresponding algorithms usually remained very specific for each molecule and question of interest.…”