Klaus R. Liedl

A QM/MM simulation method applied to the solution of Li+ in liquid ammonia

Abstract A molecular dynamics simulation method based on combined quantum mechanical and classical potentials is proposed. This method computes the interactions between particles in a focus region, we call it “Hot Spot”, at quantum chemical level within an affordable computational effort. Application to solution chemistry was examined by simulating Li + solvation in liquid ammonia. The new method yields a coordination number of 4 in contrast to 6 obtained from pair-potential simulation. Dynamical properties were found in agreement with the structural change of the solvation shell. The semi-empirical MNDO method was also tested within this approach, but proved inappropriate for the treatment of electrolyte solutions.

A critical analysis of electronic density functionals for structural, energetic, dynamic, and magnetic properties of hydrogen fluoride clusters

We present extensive computational results on density functional calculations for hydrogen fluoride species (HF)n (with 1≤n≤6) and compare them to results from other approaches and experiments, where available. Among the calculated properties we discuss equilibrium structural parameters, vibrational frequencies, electric dipole moments, IR intensities, dissociation energies, barriers for rearrangement by proton tunneling, NMR chemical shifts and spin couplings for 1H and 19F, and magnetic susceptibilities. It is found that density functional (particularly BLYP) and even more so hybrid approaches (particularly B3LYP) provide useful results. However, we show that due to some characteristic deficiencies, these are in general not competitive with more quantitative results from large basis set MP2 calculations. The calculated magnetic properties do not indicate any “aromaticity” connected to a hypothetical electronic ring current. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1695–1719, 1997

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimers disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinskis Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans.

Antiviral potential and molecular insight into neuraminidase inhibiting diarylheptanoids from Alpinia katsumadai.

At present, neuraminidase (NA) inhibitors are the mainstay of pharmacological strategies to fight against global pandemic influenza. In the search for new antiviral drug leads from nature, the seed extract of Alpinia katsumadai has been phytochemically investigated. Among the six isolated constituents, four diarylheptanoids showed in vitro NA inhibitory activities in low micromolar ranges against human influenza virus A/PR/8/34 of subtype H1N1. The most promising constituent, katsumadain A (4; IC(50) = 1.05 +/- 0.42 microM), also inhibited the NA of four H1N1 swine influenza viruses, with IC(50) values between 0.9 and 1.64 muM, and showed antiviral effects in plaque reduction assays. Considering the flexible loop regions of NA, extensive molecular dynamics (MD) simulations were performed to study the putative binding mechanism of the T-shaped diarylheptanoid 4. Docking results showed well-established interactions between the protein and the core of this novel NA-inhibiting natural scaffold, excellent surface complementarity to the simulated binding pocket, and concordance with experimentally derived SAR data.

The hydration shell structure of Li+ investigated by Born–Oppenheimer ab initio QM/MM dynamics

Abstract A combined ab initio quantum mechanical (QM) and molecular mechanical (MM) molecular dynamics simulation has been applied to study the non-additive contributions to the surroundings of Li + in water. The first hydration sphere of Li + is treated by Born–Oppenheimer ab initio quantum mechanics, while the rest is described by classical pair potentials. A tetrahedral structure of four water molecules in the first solvation shell of Li + is found by this combined QM/MM method with a valence double-zeta basis set, in contrast to the octahedral structure obtained by the traditional simulation using pair potentials.

Towards the Experimental Decomposition Rate of Carbonic Acid (H2CO3) in Aqueous Solution

Dry carbonic acid has recently been shown to be kinetically stable even at room temperature. Addition of water molecules reduces this stability significantly, and the decomposition (H2CO3 + nH2O --> (n+1)H2O + CO2) is extremely accelerated for n = 1, 2, 3. By including two water molecules, a reaction rate that is a factor of 3000 below the experimental one (10 s(-1)) at room temperature was found. In order to further remove the gap between experiment and theory, we increased the number of water molecules involved to 3 and took into consideration different mechanisms for thorough elucidation of the reaction. A mechanism whereby the reaction proceedes via a six-membered transition state turns out to be the most efficient one over the whole examined temperature range. The determined reaction rates approach experimental values in aqueous solution reasonably well; most especially, a significant increase in the rates in comparison to the decomposition reaction with fewer water molecules is found. Further agreement with experiment is found in the kinetic isotope effects (KIE) for the deuterated species. For water-free carbonic acid, the KIE (i.e., kH2CO3/kD2CO3) for the decomposition reaction is predicted to be 220 at 300 K, whereas it amounts to 2.2-3.0 for the investigated mechanisms including three water molecules. This result is therefore reasonably close to the experimental value of 2 (at 300 K). These KIEs are in much better accordance with the experiment than the KIE for decomposition with fewer water entities.

The optimal tunneling path for the proton transfer in malonaldehyde

The proton tunneling reaction in malonaldehyde at low temperatures is investigated. The principal aim of this study is to find the optimal tunneling path at 0 K in the framework of the semiclassical theory with a global optimization method. An amount of 11366 ab inito points was determined in the reaction swath (i.e., the conformational space enclosed by the minima and the transition state) of malonaldehyde. With a simulated annealing approach, the path with the smallest integral of the imaginary action through the swath from minimum to minimum was determined. Surprisingly the optimal tunneling path was found to be quite far off the large curvature tunneling path [i.e., the straight connection of the two minima large-current tunneling (LCT path)]. At the beginning, it is following the minimum energy path (MEP) (i.e. the path with the lowest energy connecting the two minima and passing through the transition state), and then it is describing a curved path through the reaction swath. This curve was determin...

The ground-state tunneling splitting of various carboxylic acid dimers

Carboxylic acid dimers in gas phase reveal ground-state tunneling splittings due to a double proton transfer between the two subunits. In this study we apply a recently developed accurate semiclassical method to determine the ground-state tunneling splittings of eight different carboxylic acid derivative dimers (formic acid, benzoic acid, carbamic acid, fluoro formic acid, carbonic acid, glyoxylic acid, acrylic acid, and N,N-dimethyl carbamic acid) and their fully deuterated analogs. The calculated splittings range from 5.3e-4 to 0.13 cm(-1) (for the deuterated species from 2.8e-7 to 3.3e-4 cm(-1)), thus indicating a strong substituent dependence of the splitting, which varies by more than two orders of magnitude. One reason for differences in the splittings could be addressed to different barriers heights, which vary from 6.3 to 8.8 kcal/mol, due to different mesomeric stabilization of the various transition states. The calculated splittings were compared to available experimental data and good agreement was found. A correlation could be found between the tunneling splitting and the energy barrier of the double proton transfer, as the splitting increases with increased strength of the hydrogen bonds. From this correlation an empirical formula was derived, which allows the prediction of the ground-state tunneling splitting of carboxylic acid dimers at a very low cost and the tunneling splittings for parahalogen substituted benzoic acid dimers is predicted.

Heteroaromatic π‑Stacking Energy Landscapes

In this study we investigate π-stacking interactions of a variety of aromatic heterocycles with benzene using dispersion corrected density functional theory. We calculate extensive potential energy surfaces for parallel-displaced interaction geometries. We find that dispersion contributes significantly to the interaction energy and is complemented by a varying degree of electrostatic interactions. We identify geometric preferences and minimum interaction energies for a set of 13 5- and 6-membered aromatic heterocycles frequently encountered in small drug-like molecules. We demonstrate that the electrostatic properties of these systems are a key determinant for their orientational preferences. The results of this study can be applied in lead optimization for the improvement of stacking interactions, as it provides detailed energy landscapes for a wide range of coplanar heteroaromatic geometries. These energy landscapes can serve as a guide for ring replacement in structure-based drug design.

Evaporation cycle experiments — A simulation of salt-induced peptide synthesis under possible prebiotic conditions

Evaporation cycles applied to dilute solutions of amino acids, Cu(II) and NaCl lead to peptides within 1–3 days. This simulation of possible coastal or laguna processes in a primitive earth environment gives further indications towards the relevance of the salt-induced peptide formation reaction in chemical evolution. The experiments were successfully applied to glycine, alanine, aspartic and glutamic acid. Besides isolated amino acids, also their mixtures with glycine as reaction partner were studied, leading to peptides for all of the aforementioned substances, as well as for valine and proline, which do not dimerize alone. Sequence preferences and some conservation of optical purity were observed.