Dynamics of organophosphate guest encapsulation in heteroleptic coordination cages.

Heteroleptic coordination cages allow the design of different host structures that can bind guest molecules within their cavities. In a previous work, the energetics of organophosphate encapsulation in palladium(II)-based heteroleptic coordination cages that differ in terms of their ability to form hydrogen bonds have been investigated [Platzek et al., Endohedrally Functionalized Heteroleptic Coordination Cages for Phosphate Ester Binding, Angew. Chem., Int. Ed. 2022, 61, e2022093]. The present work focuses on the dynamics of this system. Dynamic information is obtained through the application of a Markov state model (MSM) to unbiased multi-microsecond atomistic molecular dynamics simulations of guest binding and release. The MSM reveals that both the bound state and the binding/unbinding pathways are highly dynamic, with different types of interactions mediating the binding of the diphenylphosphate guest. Thus, the simulations highlight the dynamic nature of the nanoconfinement in the host-guest systems, with possible implications for the use of such coordination cages as catalysts.

Steering the Ultrafast Opening and Closure Dynamics of a Photochromic Coordination Cage by Guest Molecules.

Photochemical studies on supramolecular hosts that can encapsulate small guest molecules commonly focus on three aspects: photoswitching the cage to release or trap the guest, the effect of the confining environment on the guest, and light-induced exciton or charge transfer within the cage structure. Here, we exploit ultrafast spectroscopy to address how the guest alters the photoswitching characteristics of the cage. For this, the impacts of three disparate guest compounds on ring-opening or ring-closure of a dithienylethene (DTE) ligand in a photoswitchable DTE-based coordination cage are juxtaposed. The guest modulates both outcome and timescale of the cage's photodynamics, by an interplay of structural strain, heavy-atom effect, and enhancement of charge-transfer processes exercised by the guest on the photo-excited cage. The approach might prove beneficial for attuning the applicability of photoswitchable nanocontainers and desired guest compounds.

Endohedrally Functionalized Heteroleptic Coordination Cages for Phosphate Ester Binding.

Metallosupramolecular hosts of nanoscopic dimensions, which are able to serve as selective receptors and catalysts, are usually composed of only one type of organic ligand, restricting diversity in terms of cavity shape and functional group decoration. We report a series of heteroleptic [Pd2 A2 B2 ] coordination cages that self-assemble from a library of shape complementary bis-monodentate ligands in a non-statistical fashion. Ligands A feature an inward pointing NH function, able to engage in hydrogen bonding and amenable to being functionalized with amide and alkyl substituents. Ligands B comprise tricyclic aromatic backbones of different shape and electronic situation. The obtained heteroleptic coordination cages were investigated for their ability to bind phosphate diesters as guests. All-atom molecular dynamics (MD) simulations in explicit solvent were conducted to understand the mechanistic relationships behind the experimentally determined guest affinities.

Thermodynamic driving forces of guest confinement in a photoswitchable cage.

Photoswitchable cages that confine small guest molecules inside their cavities offer a way to control the binding/unbinding process through irradiation with light of different wavelengths. However, detailed characterization of the structural and thermodynamic consequences of photoswitching is very challenging to achieve by experiments alone. Thus, all-atom molecular dynamics (MD) simulations were carried out to gain insight into the relationship between the structure and binding affinity. Binding free energies of the B12F122- guest were obtained for all photochemically accessible forms of a photoswitchable dithienylethene (DTE) based coordination cage. The MD simulations show that successive photo-induced closure of the four individual DTE ligands that form the cage gradually decreases the binding affinity. Closure of the first ligand significantly lowers the unbinding barrier and the binding free energy, and therefore favours guest unbinding both kinetically and thermodynamically. The analysis of different enthalpy contributions to the free energy shows that binding is enthalpically unfavourable and thus is an entropy-driven process, in agreement with the experimental data. Separating the enthalpy into the contributions from electrostatic, van der Waals, and bonded interactions in the force field shows that the unfavourable binding enthalpy is due to the bonded interactions being more favourable in the dissociated state, suggesting the presence of structural strain in the bound complex. Thus, the simulations provide microscopic explanations for the experimental findings and provide a possible route towards the targeted design of switchable nanocontainers with modified binding properties.

Conformational Preferences of an Intrinsically Disordered Protein Domain: A Case Study for Modern Force Fields.

Molecular simulations of intrinsically disordered proteins (IDPs) are challenging because they require sampling a very large number of relevant conformations, corresponding to a multitude of shallow minima in a flat free energy landscape. However, in the presence of a binding partner, the free energy landscape of an IDP can be dominated by few deep minima. This characteristic imposes high demands on the accuracy of the force field used to describe the molecular interactions. Here, as a model system for an IDP that is unstructured in solution but folds upon binding to a structured interaction partner, the transactivation domain of c-Myb was studied both in the unbound (free) form and when bound to the KIX domain. Six modern biomolecular force fields were systematically tested and compared in terms of their ability to describe the structural ensemble of the IDP. The protein force field/water model combinations included in this study are AMBER ff99SB-disp with its corresponding water model that was derived from TIP4P-D, CHARMM36m with TIP3P, ff15ipq with SPC/Eb, ff99SB*-ILDNP with TIP3P and TIP4P-D, and FB15 with TIP3P-FB water. Comparing the results from REST2-enhanced sampling simulations with experimental CD spectra and secondary chemical shifts reveals that the ff99SB-disp force field can realistically capture the broad and mildly helical structural ensemble of free c-Myb. The structural ensembles yielded by CHARMM36m, ff99SB*-ILDNP together with TIP4P-D water, and FB15 are also mildly helical; however, each of these force fields can be assigned a specific subset of c-Myb residues for which the simulations could not reproduce the experimental secondary chemical shifts. In addition, microsecond-timescale MD simulations of the KIX/c-Myb complex show that most force fields used preserve a stable helix fold of c-Myb in the complex. Still, all force fields predict a KIX/c-Myb complex interface that differs slightly from the structures provided by NMR because several NOE-derived distances between KIX and c-Myb were exceeded in the simulations. Taken together, the ff99SB-disp force field in the first place but also CHARMM36m, ff99SB*-ILDNP together with TIP4P-D water, and FB15 can be suitable choices for future simulation studies of the coupled folding and binding mechanism of the KIX/c-Myb complex and potentially also other IDPs.