The PROPKA method for the prediction of the pKa values of ionizable residues in proteins is extended to include the effect of non‐proteinaceous ligands on protein pKa values as well as predict the change in pKa values of ionizable groups on the ligand itself. This new version of PROPKA (PROPKA 2.0) is, as much as possible, developed by adapting the empirical rules underlying PROPKA 1.0 to ligand functional groups. Thus, the speed of PROPKA is retained, so that the pKa values of all ionizable groups are computed in a matter of seconds for most proteins. This adaptation is validated by comparing PROPKA 2.0 predictions to experimental data for 26 protein–ligand complexes including trypsin, thrombin, three pepsins, HIV‐1 protease, chymotrypsin, xylanase, hydroxynitrile lyase, and dihydrofolate reductase. For trypsin and thrombin, large protonation state changes (|n| > 0.5) have been observed experimentally for 4 out of 14 ligand complexes. PROPKA 2.0 and Klebe's PEOE approach (Czodrowski P et al. J Mol Biol 2007;367:1347–1356) both identify three of the four large protonation state changes. The protonation state changes due to plasmepsin II, cathepsin D and endothiapepsin binding to pepstatin are predicted to within 0.4 proton units at pH 6.5 and 7.0, respectively. The PROPKA 2.0 results indicate that structural changes due to ligand binding contribute significantly to the proton uptake/release, as do residues far away from the binding site, primarily due to the change in the local environment of a particular residue and hence the change in the local hydrogen bonding network. Overall the results suggest that PROPKA 2.0 provides a good description of the protein–ligand interactions that have an important effect on the pKa values of titratable groups, thereby permitting fast and accurate determination of the protonation states of key residues and ligand functional groups within the binding or active site of a protein. Proteins 2008. © 2008 Wiley‐Liss, Inc.

Helicenes and heterohelicenes, which present fascinating leftor right-handed chiral helical structures (of M and P configuration respectively), have been intensively studied for their excellent self-assembling, chiroptical, photochromic, and nonlinear optical properties, as well as in asymmetric molecular recognition and synthesis, sensors, and polymer fields. [1,2] The large helicenes, such as [6]helicene, are configurationally stable at room temperature.[1] The enantiomers can be separated, stored over long periods of time, and used for the above-mentioned applications. The barrier of interconversion between the M and P enantiomers of smaller [4](hetero)helicene derivatives is however much lower as the racemization takes place rapidly in solution at room

Helicenes and heterohelicenes, which present fascinating leftor right-handed chiral helical structures (of M and P configuration respectively), have been intensively studied for their excellent self-assembling, chiroptical, photochromic, and nonlinear optical properties, as well as in asymmetric molecular recognition and synthesis, sensors, and polymer fields. [1,2] The large helicenes, such as [6]helicene, are configurationally stable at room temperature.[1] The enantiomers can be separated, stored over long periods of time, and used for the above-mentioned applications. The barrier of interconversion between the M and P enantiomers of smaller [4](hetero)helicene derivatives is however much lower as the racemization takes place rapidly in solution at room

The application of statistical simulations to the estimation of transfer free energies of pharmacologically relevant organic molecules is reported. Large-scale molecular dynamics simulations have been carried out on a series of four solutes, viz. antipyrine, caffeine, ganciclovir, and alpha-D-glucose, at the water-dodecane interface as a model of a biological water-membrane interfacial system. Agreement with experimentally determined partition coefficients is remarkable, demonstrating that free energy calculations, when executed with appropriate protocols, have reached the maturity to predict thermodynamic quantities of interest to the pharmaceutical world. The computational effort that warrants accurate, converged free energies remains, however, in large measure, incompatible with the high-throughput exploration of large sets of pharmacologically active drugs sought by industrial settings. Compared to the cost-effective, fast estimation of simple partition coefficients, the present free energy calculations, nevertheless, offer a far more detailed information about the underlying energetics of the system when the solute is translocated across the water-dodecane interface, which can be valuable in the context of de novo drug design.

Herein is reported an experimental and theoretical study of the circular dichroism properties of TRISPHAT (1) anion. ECD analysis of the [tetramethylammonium][D-1] salt confirms the absolute configuration assignment obtained through X-ray crystallographic analysis of the parent cinchonidium salt. The structure, infrared, and vibrational circular dichroism (VCD) spectra derived from density functional theory (DFT) calculations are compared with experimental data. Chirality 17:S143 -S148, 2005.