Multi-scale simulation of electrostatic channeling

One-pot multistep catalysis, also called tandem catalysis, denotes stepwise chemical reactions over sequential active sites in a single vessel. Such an approach enables efficient synthesis of various product molecules from simple precursors, and complete utilization of the energy stored in each chemical bond. Therefore, such cascade catalysis is of great significance to the manufacture of fine chemicals, the production of pharmaceutical intermediates, and electrocatalytic devices. A key factor limiting these processes is the mass transport of reaction intermediates, which in nature is found to be largely facilitated by substrate channeling, in which intermediate molecules are transferred directly to a subsequent active site instead of equilibrating to bulk environment. Electrostatically bound diffusion represents one such channeling mechanism, in which charged intermediates are transported along an oppositely charged pathway. Naturally occurring electrostatic channeling has been studied for decades, but the challenge of controlling molecular-level interactions along with catalytic kinetics has hindered its application to artificial cascades. In this work, multi-scale simulations by a combination of molecular dynamics (MD) and kinetic Monte Carlo (KMC) are utilized to quantify the overall kinetics of artificial cascades, aiming to further explore the channeling mechanism and reveal potential limitations for future cascade design. Taking advantage of this hierarchical model, the molecular complexity may be fully considered and a wide range of time and length scales can be effective covered to bridge the gap between microstructures and kinetic events.Specifically, a hopping surface diffusion mode is demonstrated by molecular dynamics simulation, wherein charged intermediate molecules are shuttled along a cationic oligopeptide bridge that is proposed to covalently conjugate hexokinase (HK) and glucose-6-phosphate dehydrogenase (G6PDH). Strong experimental evidence for the occurrence of electrostatic channeling is provided by ionic-strength dependent studies, via both simulations and experimental stop-flow lag time analysis. Specifically, simulations suggest that a balance between surface adsorption and diffusion is required for optimal channeling efficiency. To further quantify the energy associated with each elementary step in channeling process, advanced sampling methods are employed to study interactions on the cascade surface. Transition state theory is used to calculate the hopping energy barrier via a temperature-dependent study of hopping frequency. Desorption energy is calculated by umbrella sampling, further revealing ionic strength-independent Stern layer diffusion under the protection of an ionic strength-dependent diffuse layer. Intermediate hopping from the peptide bridge to its binding site on G6PDH is analyzed by transition pathway theory, which provides sufficient sampling of the interactive pathways on this 2D flexible surface. The leakage in this process is evaluated by probability analysis.Finally, overall cascade kinetics is quantified by the KMC method, integrating the MD and experiment parameters. The KMC model enables direct comparison with stop-flow lag time analysis, by evaluating the product evolution over the entire experimental time scale, including the pre-steady state. The KMC results provide good agreement with experiment in terms of ionic strength dependence. Moreover, KMC reveals several key parameters limiting overall cascade kinetics, including the strength of surface interactions, the length of channeling pathway, and the energy barrier around the artificial interface of synthetic cascade.