There are many open questions regarding the hydration of solvent-exposed, non-polar tracts and pockets in proteins. Although water is predicted to de-wet purely repulsive surfaces and evacuate crevices, the extent of de-wetting is unclear when ubiquitous van der Waals interactions are in play. The structural simplicity of synthetic supramolecular hosts imbues them with considerable potential to address this issue. To this end, here we detail a combination of densimetry and molecular dynamics simulations of three cavitands, coupled with calorimetric studies of their complexes with short-chain carboxylates. Our results reveal the range of wettability possible within the ostensibly identical cavitand pockets — which differ only in the presence/position of the methyl groups that encircle the portal to their non-polar pockets. The results demonstrate the ability of macrocycles to template water cavitation within their binding sites and show how the orientation of methyl groups can trigger the drying of non-polar pockets in liquid water, suggesting new avenues to control guest complexation.
more »
« less
Pressure Induced Wetting and Dewetting of the Nonpolar Pocket of Deep-Cavity Cavitands in Water
Hydrophobic interactions drive the binding of
nonpolar ligands to the oily pockets of proteins and supramolecular
species in aqueous solution. As such, the wetting of host
pockets is expected to play a critical role in determining the
thermodynamics of guest binding. Here we use molecular
simulations to examine the impact of pressure on the wetting
and dewetting of the nonpolar pockets of a series of deep-cavity
cavitands in water. The portals to the cavitand pockets are
functionalized with both nonpolar (methyl) and polar (hydroxyl)
groups oriented pointing either upward or inward toward the
pocket. We find wetting of the pocket is favored by the hydroxyl
groups and dewetting is favored by the methyl groups. The
distribution of waters in the pocket is found to exhibit a two-state-like equilibrium between wet and dry states with a free energy
barrier between the two states. Moreover, we demonstrate that the pocket hydration of the cavitands can be collapsed onto a unified
adsorption isotherm by assuming the effective pressures within each cavitand pocket differ by a shift pressure that depends on the
chemical identity and number of functional groups placed about the portal. These observations support the development of a twostate
capillary evaporation model that accurately describes the equilibrium between states and naturally gives rise to the effective shift
pressures observed from simulation. This work demonstrates that the hydration of host pockets can be tuned following simple design
rules that in turn are expected to impact the thermodynamics of guest complexation.
more »
« less
- Award ID(s):
- 1805167
- PAR ID:
- 10157677
- Date Published:
- Journal Name:
- The Journal of Physical Chemistry B
- ISSN:
- 1520-6106
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
We describe here the effects of metal complexation on the molecular recognition behavior of cavitands with quinoxaline walls. The nitrogen atoms of the quinoxalines are near the upper rim of the vase-like shape and treatment with Pd(II) gave 2:1 metal:cavitand derivatives. Characterization by 1 H, 13 C NMR spectroscopy, HR ESI-MS, and computations showed that the metals bridged adjacent quinoxaline panels and gave cavitands with C 2v symmetry. Both water-soluble and organic-soluble versions were prepared and their host/guest complexes with alkanes, alcohols, acids, and diols (up to C12) were studied by 1 H NMR spectroscopy. Analysis of the binding behavior indicated that the metals rigidified the walls of the receptive vase conformation and enhanced the binding of hydrophobic and even water-soluble guests, compared to related cavitands reported previously. The results demonstrated that the conformational dynamics of the cavitand were slowed by the coordination of Pd(II) and stabilized the host’s complexes.more » « less
-
Host–guest interactions are important to the design of pharmaceuticals and, more broadly, to soft materials as they can enable targeted, strong, and specific interactions between molecules. The binding process between the host and guest may be classified as a “rare event” when viewing the system at atomic scales, such as those explored in molecular dynamics simulations. To obtain equilibrium binding conformations and dissociation constants from these simulations, it is essential to resolve these rare events. Advanced sampling methods such as the adaptive biasing force (ABF) promote the occurrence of less probable configurations in a system, therefore facilitating the sampling of essential collective variables that characterize the host–guest interactions. Here, we present the application of ABF to a rod–cavitand coarse-grained model of host–guest systems to acquire the potential of mean force. We show that the employment of ABF enables the computation of the configurational and thermodynamic properties of bound and unbound states, including the free energy landscape. Moreover, we identify important dynamic bottlenecks that limit sampling and discuss how these may be addressed in more general systems.more » « less
-
The effects on the molecular recognition properties of water-soluble deep cavitand hosts upon embedding them in phosphocholine lipid bilayer environments have been studied by 2D NMR experiments. By employing suitable guests containing 19 F or 13 C nuclei that can be encapsulated inside the host, 2D EXSY NMR experiments can be used to analyze and compare the in/out guest exchange rates in aqueous solution, isotropically tumbling micelles, or magnetically ordered bicelles. These analyses show that embedding the deep cavitands in lipid bilayers slows the guest exchange rate, due to the lipids acting as a “compression sleeve” around the host, restricting guest egress. This effect also enhances guest conformations in the host that are not observed in free solution, such as axial cyclohexane conformers and ketone hydrates.more » « less
-
Octa-acid (OA) and tetra- endo -methyl octa-acid (TEMOA) are deep cavity cavitands that readily form multimeric complexes with hydrophobic guests, like n -alkanes, in aqueous solution. Experimentally, OA displays a monotonic progression from monomeric to dimeric complexes with n -alkanes of increasing length, while TEMOA exhibits a non-monotonic progression from monomeric, to dimeric, to monomeric, to dimeric complexes over the same range of guest sizes. Previously we have conducted simulations demonstrating this curious behavior arises from the methyl units ringing TEMOA's portal to its hydrophobic pocket barring the possibility for two alkane chains to simultaneously bridge between two hosts in a dimer. Here we expand our prior simulation study to consider the partially methylated hosts mono- endo -methyl octa-acid, 1,3-di- endo -methyl octa-acid, and tri- endo -methyl octa-acid to examine the emergence of non-monotonic assembly behavior. Our simulations demonstrate a systematic progression of non-monotonic assembly with increasing portal methylation. This behavior is traced to the progressive destabilization of 2 : 2 complexes (two hosts assembled with two guests) rather than stabilizing other potential host/guest complexes that could be formed.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/acs.jpcb.0c02568
