Conformational energies of reference organic molecules: benchmarking of common efficient computational methods against coupled cluster theory.

We selected 145 reference organic molecules that include model fragments used in computer-aided drug design. We calculated 158 conformational energies and barriers using force fields, with wide applicability in commercial and free softwares and extensive application on the calculation of conformational energies of organic molecules, e.g. the UFF and DREIDING force fields, the Allinger's force fields MM3-96, MM3-00, MM4-8, the MM2-91 clones MMX and MM+, the MMFF94 force field, MM4, ab initio Hartree-Fock (HF) theory with different basis sets, the standard density functional theory B3LYP, the second-order post-HF MP2 theory and the Domain-based Local Pair Natural Orbital Coupled Cluster DLPNO-CCSD(T) theory, with the latter used for accurate reference values. The data set of the organic molecules includes hydrocarbons, haloalkanes, conjugated compounds, and oxygen-, nitrogen-, phosphorus- and sulphur-containing compounds. We reviewed in detail the conformational aspects of these model organic molecules providing the current understanding of the steric and electronic factors that determine the stability of low energy conformers and the literature including previous experimental observations and calculated findings. While progress on the computer hardware allows the calculations of thousands of conformations for later use in drug design projects, this study is an update from previous classical studies that used, as reference values, experimental ones using a variety of methods and different environments. The lowest mean error against the DLPNO-CCSD(T) reference was calculated for MP2 (0.35 kcal mol-1), followed by B3LYP (0.69 kcal mol-1) and the HF theories (0.81-1.0 kcal mol-1). As regards the force fields, the lowest errors were observed for the Allinger's force fields MM3-00 (1.28 kcal mol-1), ΜΜ3-96 (1.40 kcal mol-1) and the Halgren's MMFF94 force field (1.30 kcal mol-1) and then for the MM2-91 clones MMX (1.77 kcal mol-1) and MM+ (2.01 kcal mol-1) and MM4 (2.05 kcal mol-1). The DREIDING (3.63 kcal mol-1) and UFF (3.77 kcal mol-1) force fields have the lowest performance. These model organic molecules we used are often present as fragments in drug-like molecules. The values calculated using DLPNO-CCSD(T) make up a valuable data set for further comparisons and for improved force field parameterization.

Flatness-based control approach to drug infusion for cardiac function regulation.

A new control method based on differential flatness theory is developed in this study, aiming at solving the problem of regulation of haemodynamic parameters. Actually control of the cardiac output (volume of blood pumped out by heart per unit of time) and of the arterial blood pressure is achieved through the administered infusion of cardiovascular drugs such as dopamine and sodium nitroprusside. Time delays between the control inputs and the system's outputs are taken into account. Using the principle of dynamic extension, which means that by considering certain control inputs and their derivatives as additional state variables, a state-space description for the heart's function is obtained. It is proven that the dynamic model of the heart is a differentially flat one. This enables its transformation into a linear canonical and decoupled form, for which the design of a stabilising feedback controller becomes possible. The proposed feedback controller is of proven stability and assures fast and accurate tracking of the reference setpoints by the outputs of the heart's dynamic model. Moreover, by using a Kalman filter-based disturbances' estimator, it becomes possible to estimate in real-time and compensate for the model uncertainty and external perturbation inputs that affect the heart's model.

Improper hydrogen bonded cyclohexane C-Hax···Yax contacts: theoretical predictions and experimental evidence from 1H NMR spectroscopy of suitable axial cyclohexane models.

C-H(ax)···Y(ax) contacts are a textbook prototype of steric hindrance in organic chemistry. The nature of these contacts is investigated in this work. MP2/6-31+G(d,p) calculations predicted the presence of improper hydrogen bonded C-H(ax)···Y(ax) contacts of different strength in substituted cyclohexane rings. To support the theoretical predictions with experimental evidence, several synthetic 2-substituted adamantane analogues (1-24) with suitable improper H-bonded C-H(ax)···Y(ax) contacts of different strength were used as models of a substituted cyclohexane ring. The (1)H NMR signal separation, Δδ(γ-CH(2)), within the cyclohexane ring γ-CH(2)s is raised when the MP2/6-31+G(d,p) calculated parameters, reflecting the strength of the H-bonded C-H(ax)···Y(ax) contact, are increased. In molecules with enhanced improper H-bonded contacts C-H(ax)···Y(ax), like those having sterically crowded contacts (Y(ax) = t-Bu) or contacts including considerable electrostatic attractions (Y(ax) = O-C or O═C) the calculated DFT steric energies of the γ-axial hydrogens are considerably reduced reflecting their electron cloud compression. The results suggest that the proton H(ax) electron cloud compression, caused by the C-H(ax)···Y(ax) contacts, and the resulting increase in Δδ(γ-CH(2)) value can be effected not just from van der Waals spheres compression, but more generally from electrostatic attraction forces and van der Waals repulsion, both of which are improper H-bonding components.