Carol A. Venanzi

Ab initio molecular orbital study of 1-methylsilatrane and model compounds

Abstract Ab initio molecular orbital calculations (3-21G∗) have been employed to explore bonding in two structures of 1-methylsilatrane: a solid-state structure based upon crystallographic data and a “gas-phase structure” in which the N-Si dative.bond has been artificially lengthened by 0.28 A. Despite the significant change in N-Si bond strength, there is very little change in calculated Mulliken charges. The utility of the 3-21G∗ calculations for this system was verified through comparison with 3-21G∗, 6-31G∗, other calculational studies and experimental data for NH3·SiF4, NH3·SiF(OH)3 and a variety of amine-borane adducts.

Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods

SummaryMethylphenidate (MP) binds to the cocaine binding site on the dopamine transporter and inhibits reuptake of dopamine, but does not appear to have the same abuse potential as cocaine. This study, part of a comprehensive effort to identify a drug treatment for cocaine abuse, investigates the effect of choice of calculation technique and of solvent model on the conformational potential energy surface (PES) of MP and a rigid methylphenidate (RMP) analogue which exhibits the same dopamine transporter binding affinity as MP. Conformational analysis was carried out by the AM1 and AM1/SM5.4 semiempirical molecular orbital methods, a molecular mechanics method (Tripos force field with the dielectric set equal to that of vacuum or water) and the HF/6-31G* molecular orbital method in vacuum phase. Although all three methods differ somewhat in the local details of the PES, the general trends are the same for neutral and protonated MP. In vacuum phase, protonation has a distinctive effect in decreasing the regions of space available to the local conformational minima. Solvent has little effect on the PES of the neutral molecule and tends to stabilize the protonated species. The random search (RS) conformational analysis technique using the Tripos force field was found to be capable of locating the minima found by the molecular orbital methods using systematic grid search. This suggests that the RS/Tripos force field/vacuum phase protocol is a reasonable choice for locating the local minima of MP. However, the Tripos force field gave significantly larger phenyl ring rotational barriers than the molecular orbital methods for MP and RMP. For both the neutral and protonated cases, all three methods found the phenyl ring rotational barriers for the RMP conformers/invertamers (denoted as cte, tte, and cta) to be: cte, tte> MP > cta. Solvation has negligible effect on the phenyl ring rotational barrier of RMP. The B3LYP/6-31G* density functional method was used to calculate the phenyl ring rotational barrier for neutral MP and gave results very similar to those of the HF/6-31G* method.

Reconsidering the conformational flexibility of β-cyclodextrin

Abstract Conformational analysis of β-cyclodextrin in vacuo has been carried out using two complementary searching techniques to answer the question: what is the relationship between the conformational changes in the Φ,Ψ torsional angles around the glycosidic bonds and the fluctuations of the hydroxyl pendant groups? Because of the large number of local minima on the conformation and potential energy surface of cyclodextrin, a standard systematic search involving molecular mechanics minimization at points on a regular, fixed torsional angle space grid would generate so many points as to be impractical for conformational sampling. Instead the RAMM (RAndom Molecular Mechanics) procedure, a molecular mechanics calculation based on a random walk within torsional angle space, is used here and is compared to the results of nanosecond molecular dynamics simulation. The RAMM procedure is a semi-automatic calculation of the n-dimensional potential energy surface of a molecule which combines a grid-based conformation and search for one pair of bonds with random generation of a conformational ensemble of rotatable bonds and optimization of molecular geometry. Results are presented for six conformers of low symmetry and three conformers with higher symmetry. For all cases, random sampling of the 287-dimensional hydroxy and hydroxymethyl pendant group torsional angle conformational space improved the molecular energy. Torsional angles involving the primary hydroxyl groups exhibited larger conformational freedom than those involving secondary hydroxyls. The secondary hydroxyls of the symmetric forms are involved in a homodromic O2…O3 hydrogen bonding network. The results of the RAMM modeling agree with results from molecular dynamics simulations at 300 K (1 ns), 400 K (2 ns), and at 1000 K (1 ns) with dielectric constant 1. At the two lower temperatures, the molecule fluctuates within the Φ,Ψ space at values around 0 °,0 °. The occupancy profile, drawn in two-dimensional Φ,Ψ plots, is similar for each of the seven combinations of Φi, Ψi and has a characteristic half-moon shape. A stabilizing hydrogen bond network between O2(i)…O3(i − 1) is present during the entire simulation with a consequent decrease in the mobility of HO2 and HO3 (oscillating around χ i2 ≅ −60 °, χ i3 \ t-60 ° ). No conformational transitions of these groups were observed at 300 K and the first and only reorientation (χi2 ≅ 180 °, χi3 ≅ 180 °) occurred at approximately 1.7 ns at 400 K. At 1000 K, the molecule explores regions beyond Φ,Ψ equal to 0 °,0 ° and the chair conformer of the pyranose rings is not preserved. An additional 2 ns molecular dynamics simulation at 400 K with dielectric constant 4 revealed the “flip-flop” character of O2…O3 hydrogen bonding between adjacent glucose residues.

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.

Computer-aided design of artificial enzymes: cyclic urea mimetics of alpha-chymotrypsin

We use molecular mechanics to calculate the conformational properties of a cyclic urea mimetic of alpha-chymotrypsin proposed, but not yet synthesized, by Cram and co-workers. We find that, in order to bring the structural elements of the catalytic triad into a spatial orientation suitable for proton transfer, the proposed enzyme mimetic must adopt a highly strained conformation. We redesign that part of the molecular architecture holding the catalytic triad in position and suggest two alternative enzyme mimetics. Of these, we find that the mimetic containing a fused ring structure positions the components of the catalytic triad at reasonable distances for proton transfer. We study the effect of these structural alterations on the recognition pattern presented by the enzyme mimetic to the substrate, as illustrated by the molecular electrostatic potential of the artificial enzyme.

Hierarchical clustering analysis of flexible GBR 12909 dialkyl piperazine and piperidine analogs

Pharmacophore modeling of large, drug-like molecules, such as the dopamine reuptake inhibitor GBR 12909, is complicated by their flexibility. A comprehensive hierarchical clustering study of two GBR 12909 analogs was performed to identify representative conformers for input to three-dimensional quantitative structure–activity relationship studies of closely-related analogs. Two data sets of more than 700 conformers each produced by random search conformational analysis of a piperazine and a piperidine GBR 12909 analog were studied. Several clustering studies were carried out based on different feature sets that include the important pharmacophore elements. The distance maps, the plot of the effective number of clusters versus actual number of clusters, and the novel derived clustering statistic, percentage change in the effective number of clusters, were shown to be useful in determining the appropriate clustering level.Six clusters were chosen for each analog, each representing a different region of the torsional angle space that determines the relative orientation of the pharmacophore elements. Conformers of each cluster that are representative of these regions were identified and compared for each analog. This study illustrates the utility of using hierarchical clustering for the classification of conformers of highly flexible molecules in terms of the three-dimensional spatial orientation of key pharmacophore elements.

An Ab Initio Study of the Geometry and Rotational Barrier of 4- Phenylimidazole

The molecular design of several synthetic artificial enzymes, which mimic the action of the serine proteaseα-chymotrypsin, incorporates the phenylimidazole molecular fragment to play the role of the His-57 residue in the native enzyme active site. Study of these artificial enzymes by molecular modeling techniques requires accurate torsional force field parameters for the phenylimidazole interring bond. This, in turn, requires accurate characterization of the barrier to rotation around this bond. Previous semiempirical calculations of this rotational barrier have neglected geometry optimization of the molecule at the points along the rotational pathway. The 4-phenylimidazole rotational barrier (5.6 kcal mol−1] presented here was obtained by full ab initio geometry optimization at the 3–21G level at each of the points along the rotational pathway.

Electrostatic features of molecular recognition by cyclic urea mimics of chymotrypsin

Abstract The molecular electrostatic-potential pattern was used to investigate the electrostatic features of molecular recognition by two cyclic urea mimics of the active site of α-chymotrypsin. The structures of the mimics were obtained by molecular-mechanics evaluation of the conformational potential-energy surface of the molecules. Calculations were done by using two different atomic point-charge sets in order to assess the effect of charge on the electrostatic potential pattern. The molecules studies were: (1) a “full” mimic of chymotrypsin containing the hydroxyl, imidazole, and carboxylate anion functionalities typical of the active site of the enzyme, and (2) a “partial” mimic with only the hydroxyl and imidazole functional groups. Comparison of the molecular electrostatic-potential patterns of the two mimics in both charge sets showed that the largest differences were due to the structural addition of the carboxylate anion, rather than any particular differences in the choice of atomic point charge. For the full mimic, the pattern was essentially dominated by the negative charge on the carboxylate. Small structural changes which optimized the orientation of the catalytic components had little effect on the electrostatic potential pattern of the molecule. In the absence of the anionic functionality, greater differences were noted in the electrostatic potential pattern of the partial mimic in the two charge sets. The choice of atomic point charge was seen to influence the hydrogen-bonding pattern of the hydroxyl and imidazole moieties, resulting in differences in the spatial orientation of the electrostatic potential minima. In general, both charge sets produced molecular electrostatic-potential patterns which indicated that long-range electrostatic interactions would direct the cationic end of the substrate into the electron-rich binding site. However, specific local features of the electrostatic potential pattern were found to depend on point-charge set through the influence of charge on the hydrogen-bonding pattern.

Singular value decomposition of torsional angles of analogs of the dopamine reuptake inhibitor GBR 12909

Analysis of large, flexible molecules, such as the dopamine reuptake inhibitor GBR 12909 (1), is complicated by the fact that they can take on a wide range of closely related conformations. The first step in the analysis is to classify the conformers into groups. Here, Singular Value Decomposition (SVD) was used to group conformations of GBR 12909 analogs by the similarity of their nonring torsional angles. The significance of the present work, the first application of SVD to the analysis of very flexible molecules, lies in the development of a novel scaling technique for circular data and in the grouping of molecular conformations using a technique that is independent of molecular alignment. Over 700 conformers each of a piperazine (2) and piperidine (3) analog of 1 were studied. Analysis of the score and loading plots showed that the conformers of 2 separate into three large groups due to torsional angles on the naphthalene side of the molecule, whereas those of 3 separate into nine groups due to torsional angles on the bisphenyl side of the molecule. These differences are due to nitrogen inversion at the unprotonated piperazinyl nitrogen of 2, which results in a different ensemble of conformers than those of 3, where no inversion is possible at the corresponding piperidinyl carbon.

Molecular Recognition by Cyclic Urea Mimetics of α‐Chymotrypsina

In an attempt to elucidate the molecular basis of enzyme catalysis, much effort has been directed to the experimental design of compounds that mimic the substrate specificity and rate acceleration of the serine proteases. Because of substantial synthetic difficulties, the existing mimetics lack the full triad of catalytic residues and so model only part of the hydrolysis mechanism of or-chymotrypsin. Our work aims a t construction of the full catalytic structure of the artificial enzymes through computer modeling and at comparison of molecular interactions within the enzyme-substrate complex for both natural and artificial enzymes. Our preliminary work’ investigated the degree of structural preorganization and electrostatic complementarity for substrate binding exhibited by a cation-binding precursor, structure 7 of ref. 2, of a cyclic urea mimetic, structure 3 of ref. 3, of chymotrypsin. In this paper, we study these properties for the cyclic urea compound3 found to mimic a-chymotrypsin in accelerating the rate of acyl transfer from substrates. This mimetic differs from the precursor chiefly in the addition of an m-methylenehydroxy phenyl substituent to an anisole ring of the macrocycle; it is this substituent which mimics the action of the serine 195 in a-chymotrypsin. The methodology has been described in detail.’ We investigate the degree of conformational change upon substrate binding by using molecular mechanics to calculate the structures of the uncomplexed and complexed artificial enzyme. We find that the macrocycle of the mimetic undergoes very little conformational change upon complexation with the L-alanyl p-nitrophenyl ester cation; the average change in position of the cyclic urea nitrogens and oxygens and methoxy group oxygens that line the macrocyclic cavity is less than 1 8,. The oxygen of the m-methylenehydroxy phenyl substituent moves 3.6 8, from its position in the “native” structure to that in the complex. In the complex, this oxygen is found to be 3.5 8, from the carbonyl carbon of the substrate in position for nucleophilic attack. We investigate the electrostatic complementarity of the cyclic urea enzyme mimetic for its substrate by calculating the molecular electrostatic potential patterns of the complexing partners. FIGURES 1 and 2 show the electrostatic potential patterns calculated in the z = 2 8, plane for the enzyme mimetic and substrate, respectively. Comparison of the figures shows that the enzyme mimetic provides an electron-rich cation binding site in the center of the macrocycle (indicated by large negative values of the potential) which is complemented by the large positive potential of the ammonium group of the substrate which binds in the pocket.