Thomas J. Venanzi

The application of stereolithography to the fabrication of accurate molecular models.

The process of stereolithography, which automatically fabricates plastic models from designs created in certain computer-aided design programs, has been applied to the production of accurate plastic molecular models. Atomic coordinates obtained from quantum mechanical calculations and from neutron diffraction data were used to locate spheres in the I-DEAS CAD program with radii proportional to the appropriate van der Waals radii. The sterolithography apparatus was used to build the models using a photosensitive liquid resin, resulting in hard plastic models that accurately represent the computed or experimental input structures. Three examples are given to illustrate how the models can be used to interpret experimental structure-activity data for systems of biological importance or host-guest chemistry: (1) Interpretation of kinetic data for the formation of a stable blocking complex between amiloride analogs and the epithelial sodium channel, (2) interpretation of binding and neural activity data for the interaction of certain amino acids and their analogs at the L-alanine taste receptor of the channel catfish, and (3) interpretation of shape selectivity and rate acceleration in cyclodextrin catalysis using models of the neutron diffraction structure of beta-cyclodextrin and of the transition state for the cleavage of phenyl acetate by the secondary hydroxyl oxygen of beta-cyclodextrin.

Computational analysis of binding affinity and neural response at the L-alanine receptor.

SummaryA model of analogue-receptor binding is developed for the l-alanine receptor in the channel catfish using the AM1-SM2 and ab initio SCRF computational methods. Besides interactions involving the zwitterionic moiety of the amino acid analogue and complementary subsites on the receptor, the model suggests the presence of a hydrophobic pocket with dispersion interactions between the receptor and the residue on the amino acid analogue. Conformational analysis suggests not only a small compact active site on the receptor, but also that the analogues with the highest affinity occupy nearly identical regions of space. Although the binding interaction is dominated by the ionic terms, AM1-SM2 calculations indicate that free energy terms associated with cavity formation, solvent reorganization, and dispersion interactions can be correlated to activation and neural response. From a consideration of this model, molecular features of the analogues that are important for binding and neural response were deduced and other analogues or ligands were developed and tested.

Barriers to CC rotation in molecules with CC and CN conjugated bonds: a molecular orbital study

Abstract The barriers to CC rotation in two systems, (E)-acrolein oxime and (E)-vinylimine, with CC and CN bonds in conjugation are determined using high level ab initio molecular orbital theory. 6-31G*//6-31G* and MP2/6-31G*//MP2 optimizations indicate that the CCCN torsional barriers in both molecules are generally comparable in energy to the CCCO torsional barrier in acrolein. However, the torsional barrier in (E)-acrolein oxime exhibits an almost flat conformational energy region between 0° and 30°. This latter result is not affected by changes in the CNOH angle or methyl substitution at the aldoxime or vinyl carbon.

A molecular electrostatic-potential study of acesulfame

Abstract Molecular electrostatic-potential maps are reported for the anionic and neutral forms of acesulfame (6-methyl-1,2,3-oxathiazin-4(3 H )-one-2,2-dioxide), a sweetener structurally similar to saccharin. The maps generated by methods based on a minimum basis set (STO-3G) and on a polarization basis set (3-21G*) are almost identical with respect to their contour levels. From the contour maps, broad and deep electrostatic-potential minima were found near the SO 2 and NC=O functionalities in the anion. The electrostatic potential minima directly correspond to the reactive sites proposed by Jakinovich for the interaction fo saccharin with its receptor.

On the time evolution of a born-adiabatic molecular state

Abstract Time-dependent perturbation theory is applied to the problem of a “Born-adiabatic molecule” evolving in time when subject to an external time-dependent perturbation. The treatment uses double perturbation theory within the Dirac variations-of-constants method to correct both for non-adiabaticity and external perturbations. In the case of resonance non-adiabatic corrections can become large while away from resonance the wavefunction can be a time-dependent adiabatic wavefunction.