Reconstructing reactivity in dynamic host-guest systems at atomistic resolution: amide hydrolysis under confinement in the cavity of a coordination cage

Abstract

Spatial confinement is widely employed by nature to attain unique efficiency in controlling chemical reactions. Notable examples are enzymes, which selectively bind reactants and exquisitely regulate their conversion into products. In an attempt to mimic natural catalytic systems, supramolecular metal-organic cages capable of encapsulating guests in their cavity and of controlling/accelerating chemical reactions under confinement are attracting increasing interest. However, the complex nature of these systems, where reactants/products continuously exchange in-and-out of the host, makes it often difficult to elucidate the factors controlling the reactivity in dynamic regimes. As a case study, here we focus on a coordination cage that can encapsulate amide guests and enhance their hydrolysis by favoring their mechanical twisting towards reactive molecular configurations under confinement. We designed an advanced multiscale simulation approach that allows us to reconstruct the reactivity in such host-guest systems in dynamic regimes. In this way, we can characterize amide encapsulation/expulsion in/out of the cage cavity (thermodynamics and kinetics), coupling such host-guest dynamic equilibrium with characteristic hydrolysis reaction constants. All computed kinetic/thermodynamic data are then combined, obtaining a statistical estimation of reaction acceleration in the host-guest system that is found in optimal agreement with the available experimental trends. This shows how, to understand the key factors controlling accelerations/variations in the reaction under confinement, it is necessary to take into account all dynamic processes that occur as intimately entangled in such host-guest systems. This also provides us with a flexible computational framework, useful to build structure-dynamics-property relationships for a variety of reactive host-guest systems.

Fig. 1. The host–guest systems studied in this work. (a, top) The octahedral coordination cage 1 used as a reference in this work is composed of four panel ligands (2,4,6-tris(4-pyridyl)-1,3,5-triazine) and six metal corners (cis-endcapped Pd(ii) complexes): chemical structure on the left and AA model on the right. (a, bottom) Chemical structure of amide guest 2 and of pirine co-guest 3. AA models are reported on the right of each guest structure (cis and trans isomers are shown for 2). (b, top) The hydrolysis reaction of the amide bond of 2. (b, bottom) Experimentally observed percentage of hydrolyzed 2 over time. Conversion data are reported for the hydrolysis of 2 free in solution (in blue), in the case when two 2 guests are co-encapsulated in cage 1 (black), and for 2 co-encapsulated with co-guest 3 in cage 1 (in red: ∼14× hydrolysis acceleration compared to the blue curve).

Fig. 2. Insights into the host–guest complexes at atomistic resolution. (a) Free-energy surfaces (FESs) computed from the equilibrium MD trajectories, showing the most favorable complex configurations as a function of the contacts between 1 and 2 (x axis) and of the solvent accessible surface srea (SASA) of 2 within the cage (y axis). FESs are reported respectively for 2_trans (top) and 2_cis (bottom) co-encapsulated with co-guest 3 in the cage. For each case, a representative scheme is shown of the encapsulated structures. (b) Histogram calculated from the equilibrium MD trajectories of the distance between the geometric center of cage 1 and the center of 2. (c) Histogram of the contacts between 1 and 2. (d) Histogram of the SASA of 2 under different complexation conditions (dotted distributions at large SASA values for the free guests in solution are reported for comparison). (d) Number of contacts between the oxygen atom in the amide of 2 and the water molecules in system. A color scale is used in panels (b–e) to show increasing crowding conditions for 2 within the cage.

Fig. 3. Conformers and reactivity of 2. (a) Isomerization of 2 in the cage, co-encapsulated with 3 (left: trans-2, right: cis-2). (b) Free energy profiles (shown as smoothed fits between the computed critical points) for the isomerization of 2 (i) when it is free in solution (dotted curve, cis in pink), (ii) when 2 is encapsulated in 1 (dashed curve, cis in dark pink), (iii) when it is co-encapsulated with another (trans) 2 guest in cage 1 (dot-dashed curve, cis in light red), and (iv) when 2 is encapsulated in 1 together with the co-guest 3 (solid curve, cis state in light red). The data show that increasing crowding stabilizes more and more of the reactive 2 conformations (e.g., cis) in the cage cavity. Right secondary y axis: relative probabilities (P^conf_ω) of the different conformations (ω) of 2 in the various host–guest systems calculated based on the ΔG values extracted from WT-MetaD simulations. (c) Reaction scheme modelling the first step of the hydrolysis, where the oxydrile anion (OH⁻) approaches the amide group (state R) attacking the carbonyl group (formation of the transition intermediate TI). (d) Schemes of free energy profiles (shown as smoothed fits between the computed critical points) for oxydrile attack along the reaction coordinate as a function of the ω dihedral of 2 different values. The cyan profile refers to 2 in trans conformation, the red one refers to the reaction when 2 is cis, while the violet profile refers to the free energy profile of a cis-distorted configuration of 2 with ω = π/4. A relative reactivity score for each amide conformer (χ_ω), normalized based on the maximum measured value (i.e., that for ω = π/4, set to 1), is associated with the simulated conformers of 2 (right secondary y axis).

Fig. 4. Equilibrium and kinetics of amide guest encapsulation/expulsion in/out of the cage cavity. (a) Equilibrium and kinetics for the encapsulation/expulsion of 2_trans in/out of the cage when 1 is also hosting guest 3. Above and below the arrows of the equilibrium reaction are respectively the reported kinetic constants k_off and k_on estimated from the WT-MetaD simulations. The k_on values are also reported considering the concentration present in the system (in brackets). (b) Equilibrium and kinetics for the encapsulation/expulsion of 2_cis in/out of the cage cavity when 1 is also hosting guest 3. (c) Free energy differences and barriers (ΔG and ΔG^‡) associated with the encapsulation/expulsion in the cavity of 2 when 1 is also hosting 3 (solid curves) or when 1 does not contain any other guests (dashed curves). Free energy profiles are shown as smoothed fits between the computed critical points.

Fig. 5. Reaction acceleration in a dynamic host–guest system. (a) Full dynamic representation scheme of the investigated host–guest system, showing the processes that need to be taken into account to rationalize the reaction acceleration observed experimentally. (b) Computed reaction acceleration for the various investigated host–guest systems: the hydrolysis acceleration index, a, is expressed relative to reactivity of the 2 guest alone in solution (see eqn (1)–(6)). (c) Correlation between the reaction acceleration, a, computed from the simulations and the acceleration measured experimentally (linear fit reported by the dashed line). (d–h) Relationships between the computed reaction acceleration a and various characteristic parameters of the host–guest systems: (d) relative probability of finding the 2_cis conformer over the 2_trans conformer in solution vs. in the different host–guest complexes (dashed line: exponential fit); (e) encapsulation free energy ΔG_enc of the 2_cis conformer in the different complexes (exponential fit reported by the dashed line); (f) the weighted number of contacts between the host and the guest, evaluated as the product of the peak position of the distribution shown in Fig. 2c and its height; (g) the reduction in the solvent accessible surface area (SASA) of the 2_cis guest in the different encapsulation complexes vs. when this is in solution (an indirect measure of the solvophobic effect, showing no clear correlation).