Role of Explicit Solvation in Computational Modeling of Chemical Reactions: Mechanism of Cu(I) Transfer Between...

Solvation plays important roles in controlling the thermodynamic and kinetic aspects of chemical reactions. The conventional approaches to treat solvation via electronic structure methods are likely to become inadequate, when the reacting solutes have strong electrostatic and hydrogen bonding interactions with the solvent and undergo significant structural changes during the course of the reaction. In this article, we present evidence of such solvent and structural effects in the computational study of the Cu(I) transfer reaction between thiolate-based chelators dithiobutylamine (DTBA) and dithiotheritol (DTT) in water, inspired from biological copper trafficking phenomena. We propose a general solution to the problem by combining classical molecular dynamics (MD) simulations of the bulk system and static quantum chemistry calculations. The fluctuating solvation shell was estimated from MD, and energetics was assessed by averaging QM energies of a series of molecular clusters constructed from the MD snapshots. Applying this approach, we propose a reaction pathway with estimates of relative intermediate stabilities and barriers, which suggest the overall reaction to be reversible in nature and likely to go through both two and three coordinated intermediates, confirming previous studies of similar protein analogues. An interesting fact that emerged from our study was the strong indication that the rate-determining step is the deprotonation of initial thiol bound Cu(I) complex, without involving any Cu(I)-S bonds. The proposed method will lead to a better treatment of solvations, and these mechanistic insights will aid our understanding of biological copper(I) trafficking.