Linear free energy relations and solvent effects for complexes ofm-cresol and various bases

The enthalpies, entropies, and equilibrium constants for the hydrogen bonded complexes of m-cresol with ten bases in cyclohexane solvent have been determined by calorimetric and spectroscopic methods. The logarithm of the equilibrium constant correlates well with the dipole moment of the base and the solvatochromic parameter which measures the electron donating ability of the base. The enthalpy and entropy data show that the dipole term does not enter into the log K correlation as a consequence of electrostatic interactions between acid and base in the complex. The free base-solvent interaction, which appears to be dipolar in origin, reduces the entropy of the free base and hence contributes to a favorable entropy change for complex formation. The present data are compared to previously reported data obtained in CCl₄ solvent. Solvent effects on the thermodynamic parameters in CCl₄ and cyclohexane appear to be related to dipolar interactions by m-cresol and the bases with the two solvents.     

Temperature artifacts in protein structures bias ligand-binding predictions

X-ray crystallography is the gold standard to resolve conformational ensembles that are significant for protein function, ligand discovery, and computational methods development. However, relevant conformational states may be missed at common cryogenic (cryo) data-collection temperatures but can be populated at room temperature. To assess the impact of temperature on making structural and computational discoveries, we systematically investigated protein conformational changes in response to temperature and ligand binding in a structural and computational workhorse, the T4 lysozyme L99A cavity. Despite decades of work on this protein, shifting to RT reveals new global and local structural changes. These include uncovering an apo helix conformation that is hidden at cryo but relevant for ligand binding, and altered side chain and ligand conformations. To evaluate the impact of temperature-induced protein and ligand changes on the utility of structural information in computation, we evaluated how temperature can mislead computational methods that employ cryo structures for validation. We find that when comparing simulated structures just to experimental cryo structures, hidden successes and failures often go unnoticed. When using structural information in ligand binding predictions, both coarse docking and rigorous binding free energy calculations are influenced by temperature effects. The trend that cryo artifacts limit the utility of structures for computation holds across five distinct protein classes. Our results suggest caution when consulting cryogenic structural data alone, as temperature artifacts can conceal errors and prevent successful computational predictions, which can mislead the development and application of computational methods in discovering bioactive molecules.

Temperature artifacts in protein structures impact the utility of structural information in computation by misleading validation and application of computational methods in discovering bioactive molecules.     

On the applicability of Kramers-Kronig relations for ultrasonic attenuation obeying a frequency power law

In the recent literature concern has been raised regarding the validity of Kramers-Kronig relations for media with ultrasonic attenuation obeying a frequency power law. It is demonstrated, however, that the Kramers-Kronig dispersion relations for application to these types of media are available. The developed dispersion relations are compared with measurements on several liquids, and agreement is found to better than 1 m/s over the experimentally available bandwidth. A discussion regarding the validity of these dispersion relations, in particular how the dispersion relations relate to the so-called Paley-Wiener conditions, forms the conclusion.     

Enantioselective synthesis of (-)-jiadifenin, a potent neurotrophic modulator

The first enantioselective synthesis of (-)-jiadifenin (1), a potent neurite outgrowth promoter isolated from the Illicium species, is described. The synthetic strategy builds upon bicyclic motif 6, which represents the AB ring of the natural product and proceeds in 19 steps and 1.1% overall yield. Key to our approach is a Mn(III)-mediated oxidation reaction of A ring that, following a regio- and diastereoselective α-hydroxylation and methylation sequence, produces the desired functionalities of (-)-jiadifenin. The effect of synthetic 1 in NGF-mediated neurite outgrowth was also measured in PC-12 cells.     

Treating entropy and conformational changes in implicit solvent simulations of small molecules

Implicit solvent models are increasingly popular for estimating aqueous solvation (hydration) free energies in molecular simulations and other applications. In many cases, parameters for these models are derived to reproduce experimental values for small molecule hydration free energies. Often, these hydration free energies are computed for a single solute conformation, neglecting solute conformational changes upon solvation. Here, we incorporate these effects using alchemical free energy methods. We find significant errors when hydration free energies are estimated using only a single solute conformation, even for relatively small, simple, rigid solutes. For example, we find conformational entropy (TDeltaS) changes of up to 2.3 kcal/mol upon hydration. Interestingly, these changes in conformational entropy correlate poorly (R2 = 0.03) with the number of rotatable bonds. The present study illustrates that implicit solvent modeling can be improved by eliminating the approximation that solutes are rigid.     

Shear waves in viscoelastic wormlike micellar fluids over a broad concentration range

Low frequency (61 Hz) shear wave speeds have been measured in viscoelastic wormlike micellar (WM) fluids for a concentration range of 20/12-500/300 mM CTAB/NaSAL where CTAB is the surfactant and NaSAL is the salt and the concentration ratio was fixed at 0.6 for all experiments. The birefringent property of the WM fluids was exploited to visually track the the shear pulse using crossed optical polarizing filters and high speed video. Several scalings of shear wave speed as a function of concentration were discovered: c(s) ~ √C for 20-200 mM and c(s) ~ C for higher concentrations, but with a break in the slope at 400 mM CTAB. Over this full concentration range, the shear wave speed varied from 0.08-0.7 m/s. The shear wave speed was also found to be sensitive to the time between fluid synthesis and measurement indicating a long equilibrium time. Further, comparison with elastic and loss moduli obtained from rheology data show that shear wave propagation is dominated by the elastic modulus for this frequency range. Also briefly discussed are potential applications of this fluid in elastography.     

Shear waves in viscoelastic wormlike micellar fluids

Low frequency (61 Hz) shear wave speeds have been measured in viscoelastic wormlike micellar (WM) fluids for a concentration range of 20/12-160/96 mM CTAB/NaSAL. The strain induced birefringence of the WM fluids was exploited to optically track the shear pulse using crossed polarizing filters and high speed video. It was found that shear speed increases roughly linearly with concentration at a rate of 3.5 mm s(-1) mM(-1) CTAB. Further, comparison with elastic and loss moduli obtained from rheology data show that shear wave propagation is dominated by the elastic modulus for this frequency range.