Water plays a dynamical role in a hydrogen-bonded, hexameric supramolecular assembly.

The hexameric resorcin[4]arene supramolecular assembly has attracted significant interest as a self-assembled capsule that exhibits dynamic host-guest chemistry. Many studies have been carried out to investigate the structure and thermodynamics of the assembly, but considerably less is known about its dynamical properties. Here, molecular dynamics simulations are used to investigate the timescales of water encapsulation in this assembly in wet chloroform. We have previously shown [A. Katiyar et al., Chem. Commun. 2019, 55, 6591-6594] that at low water content there are three distinct populations of water molecules present, while at higher water content an additional population, long water chains interacting with the assembly, appears. The relative free energies of these different water positions are calculated and time correlation functions are used to determine the timescales for interconversion between the populations. This analysis demonstrates that the water molecules are in rapid exchange with each other on timescales of tens of ps to a few ns, and suggests that water molecules might be acting as a critical component in the guest exchange mechanism.

Water plays a diverse role in a hydrogen-bonded, hexameric supramolecular assembly.

The interactions between water and a hexameric resorcin[4]arene assembly formed in wet chloroform are examined by molecular dynamics simulations of the diffusion coefficients. It is found that the water diffusion coefficients provide a route to understanding the degree of water association with the assembly. The simulated diffusion coefficients are in excellent agreement with prior measurements and the diffusion data are well described by a simple adsorption model. This analysis demonstrates that a significant number of waters are encapsulated within the assembly or hydrogen-bonded to its exterior, consistent with and elucidated by a direct examination of the water molecules in the simulations.

Reorientation of Isomeric Butanols: The Multiple Effects of Steric Bulk Arrangement on Hydrogen-Bond Dynamics.

Molecular dynamics simulations are used to investigate OH reorientation in the four isomeric butanols in their bulk liquid state to examine the influence of the arrangement of the steric bulk on the alcohol reorientational and hydrogen-bond (H-bond) dynamics. The results are interpreted within the extended jump model in which the OH reorientation is decomposed into contributions due to "jumps" between H-bond partners and "frame" reorientation of the intact H-bonded pair. Reorientation is fastest in iso-butanol and slowest in tert-butanol, while sec- and n-butanol have similar reorientation times. This latter result is a fortuitous cancellation between the jump and frame reorientation in the two alcohols. The extended jump model is shown to provide a quantitative description of the OH reorientation times. A detailed analysis of the jump times shows that a combination of entropic, enthalpic, and dynamical factors, including transition state recrossing effects, all play a role. A simple model based on the liquid structure is proposed to estimate the energetic and entropic contributions to the jump time. This represents the groundwork for a predictive model of OH reorientation in alcohols, but additional studies are required to better understand the frame reorientation and transition state recrossing effects.

Solvation and spectra of a charge transfer solute in ethanol confined within nanoscale silica pores.

The free energy and electronic fluorescence spectra of a model solute solvated by ethanol in a nanoscale silica pore are examined as a function of the solute position, with the aim of improving our understanding of solvation in nanoconfined environments. The results indicate that the position distribution of the solute depends on its dipole moment as well as on the surface interactions of the silica pore, i.e., hydrophilic or hydrophobic (uncharged). Further, the solute fluorescence spectrum is a function of the solute position in the hydrophilic pore, but is independent of position in the hydrophobic pore. The origins of these results are investigated, including by decomposition of the free energy as a function of solute position into the contributing interactions. The implications for time-dependent fluorescence (TDF) experiments, used commonly to probe solvation dynamics in nanoconfined solvent systems, are considered. The possible role of chromophore diffusion in TDF measurements, and chemistry in nanoconfined liquids more broadly, is given particular emphasis.

On the reorientation and hydrogen-bond dynamics of alcohols.

The mechanism of the OH bond reorientation in liquid methanol and ethanol is examined. It is found that the extended jump model, recently developed for water, describes the OH reorientation in these liquids. The slower reorientational dynamics in these alcohols compared to water can be explained by two key factors. The alkyl groups on the alcohol molecules exclude potential partners for hydrogen bonding exchanges, an effect that grows with the size of the alkyl chain. This increases the importance of the reorientation of intact hydrogen bonds, which also slows with increasing size of the alcohol and becomes the dominant reorientation pathway.

Enzyme activity of phosphatase of regenerating liver is controlled by the redox environment and its C-terminal residues.

Phosphatase of regenerating liver-1 (PRL-1) belongs to a unique subfamily of protein tyrosine phosphatases (PTPases) associated with oncogenic and metastatic phenotypes. While considerable evidence supports a role for PRL-1 in promoting proliferation, the biological regulators and effectors of PRL-1 activity remain unknown. PRL-1 activity is inhibited by disulfide bond formation at the active site in vitro, suggesting PRL-1 may be susceptible to redox regulation in vivo. Because PRL-1 has been observed to localize to several different subcellular locations and cellular redox conditions vary with tissue type, age, stage of cell cycle, and subcellular location, we determined the reduction potential of the active site disulfide bond that controls phosphatase activity to improve our understanding of the function of PRL-1 in various cellular environments. We used high-resolution solution NMR spectroscopy to measure the potential and found it to be -364.3 +/- 1.5 mV. Because normal cellular environments range from -170 to -320 mV, we concluded that nascent PRL-1 would be primarily oxidized inside cells. Our studies show that a significant conformational change accompanies activation, suggesting a post-translational modification may alter the reduction potential, conferring activity. We further demonstrate that alteration of the C-terminus renders the protein reduced and active in vitro, implying the C-terminus is an important regulator of PRL-1 function. These data provide a basis for understanding how subcellular localization regulates the activity of PRL-1 and, with further investigation, may help reveal how PRL-1 promotes unique outcomes in different cellular systems, including proliferation in both normal and diseased states.

X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-CoA.

Biosynthesis of the isoprenoid precursor, isopentenyl diphosphate, is a critical function in all independently living organisms. There are two major pathways for this synthesis, the non-mevalonate pathway found in most eubacteria and the mevalonate pathway found in animal cells and a number of pathogenic bacteria. An early step in this pathway is the condensation of acetyl-CoA and acetoacetyl-CoA into HMG-CoA, catalyzed by the enzyme HMG-CoA synthase. To explore the possibility of a small molecule inhibitor of the enzyme functioning as a non-cell wall antibiotic, the structure of HMG-CoA synthase from Enterococcus faecalis (MVAS) was determined by selenomethionine MAD phasing to 2.4 A and the enzyme complexed with its second substrate, acetoacetyl-CoA, to 1.9 A. These structures show that HMG-CoA synthase from Enterococcus is a member of the family of thiolase fold enzymes and, while similar to the recently published HMG-CoA synthase structures from Staphylococcus aureus, exhibit significant differences in the structure of the C-terminal domain. The acetoacetyl-CoA binary structure demonstrates reduced coenzyme A and acetoacetate covalently bound to the active site cysteine through a thioester bond. This is consistent with the kinetics of the reaction that have shown acetoacetyl-CoA to be a potent inhibitor of the overall reaction, and provides a starting point in the search for a small molecule inhibitor.