V.S.R. Rao

Anomeric effect in sulfur-containing systems: An Ab-initio study

Abstract The anomeric effect in Sue5f8Cue5f8S and Oue5f8Cue5f8S systems was studied by using closed-shell Hartree-Fock theory. A comparison of the STO-3G level with the 4–31G and 6–31G* levels was performed for the Oue5f8Cue5f8O system, and the STO-3G level found adequate for study of the anomeric effect. Optimization of bond lengths and angles was conducted at the STO-3G level and limited studies were made at the 4–31G level. The nature of the torsional potential curves is compared for the Oue5f8Cue5f8O, Oue5f8Cue5f8S, and Sue5f8Cue5f8S systems. The possible reasons for the decreased anomeric effect in sulfur systems are discussed.

The conformation of glycans of the oligo-D-mannosidic type, and their interaction with concanavalin A: a computer-modelling study.

The favored conformations of glycans of the oligo-D-mannosidic type have been determined by using empirical energy calculations. An interesting aspect is that the alpha-(1----3)-linked terminal D-mannose residue of the outer trimannosidic core fragment, in all the conformations which fall within 5 kcal.mol-1 of the global minimum, always lies close to the chitobiose core. These models are in general agreement with the available n.m.r. data. The probable modes of binding of these glycans to concanavalin A (Con A) were determined, by using a computer-modelling technique which identifies the positions for the different conformers of the carbohydrate in the binding site of Con A, based on stereochemical considerations. These studies showed that Con A can bind only to two of the three terminal D-mannose residues in these glycans, because the D-mannose residue which lies close to the chitobiose core is inaccessible for the binding of Con A. Of these two terminal D-mannose residues, the alpha-(1----6)-linked D-mannose may bind the more strongly. Furthermore, it is shown that the internal D-mannose residue will, at best, interact very weakly with the carbohydrate-binding site of Con A. These results rationalize well the available data on the binding affinity of these glycans to Con A. They further support the conclusion that the binding affinity of a glycan to Con A does not depend on the number in the glycan, of D-mannose residues which possess free 3-, 4-, and 6-hydroxyl groups, but, rather, on the accessibility of these residues to Con A.

Ab initio SCF—MO study of the molecular structures of aminomethanol, aminesulfonic acid and N-methyl-sulfamate

Abstract Ab initio MO studies at the STO-3G and the 4-31G level are reported for aminomethanol (H2NCH2OH), aminesulfonic acid (H2NSO3H) and N-methylsulfamate (CH3NHSO3−). The potential energy surface of aminomethanol is compared with that of methanediol and the origin of “reverse anomeric effect” is discussed. The potential energy surface of aminesulfonic acid is compared with that of aminomethanol and sulfuric acid. The favored conformations are analysed in terms of the interaction of polar bonds and the dipoles on the atoms. Various contributions to the potential energy are analysed by decomposing the potential into three term Fourier components. A general survey is made of the effect of bond length and bond angle optimisation on the conformational energies of various anomeric systems.

Interaction of substrate uridyl 3',5'-adenosine with ribonuclease A: a molecular dynamics study

A wealth of information available from x-ray crystallographic structures of enzyme-ligand complexes makes it possible to study interactions at the molecular level. However, further investigation is needed when i) the binding of the natural substrate must be characterized, because ligands in the stable enzyme-ligand complexes are generally inhibitors or the analogs of substrate and transition state, and when ii) ligand binding is in part poorly characterized. We have investigated these aspects in the binding of substrate uridyl 3,5-adenosine (UpA) to ribonuclease A (RNase A). Based on the systematically docked RNase A-UpA complex resulting from our previous study, we have undertaken a molecular dynamics simulation of the complex with solvent molecules. The molecular dynamics trajectories of this complex are analyzed to provide structural explanations for varied experimental observations on the ligand binding at the B2 subsite of ribonuclease A. The present study suggests that B2 subsite stabilization can be effected by different active site groups, depending on the substrate conformation. Thus when adenosine ribose pucker is O4-endo, Gln69 and Glu111 form hydrogen-bonding contacts with adenine base, and when it is C2-endo, Asn71 is the only amino acid residue in direct contact with this base. The latter observation is in support of previous mutagenesis and kinetics studies. Possible roles for the solvent molecules in the binding subsites are described. Furthermore, the substrate conformation is also examined along the simulation pathway to see if any conformer has the properties of a transition state. This study has also helped us to recognize that small but concerted changes in the conformation of the substrate can result in substrate geometry favorable for 2,3 cyclization. The identified geometry is suitable for intraligand proton transfer between 2-hydroxyl and phosphate oxygen atom. The possibility of intraligand proton transfer as suggested previously and the mode of transfer before the formation of cyclic intermediate during transphosphorylation are discussed.

An ab initio study of the β-lactam structure

Model compounds representing the p-lactam antibiotics have been studied by ab initio quantum chemical methods. The peptide bond length is optimized at the STO-3G level in formamide as a function of the angles at carbon and nitrogen. All ring bonds and angles in β-lactam and the peptide bond in vinyl β-lactam are optimized as a function of the external angles at nitrogen. The optimized peptide bond lengths in these model compounds compare well with the observed bond lengths in crystal structures and with their biological activities. The peptide bond is found to be sensitive to the angles at nitrogen in β-lactam and to the presence of an adjacent double bond. The energies of p-lactam conformers are studied at the 4-31G level as a function of the external angles at nitrogen; the planar form is predicted to be the most stable structure.

Theoretical studies on the conformations of aldopentopyranose tetraacetates

Abstract The net charges on various atoms of aldohexopyranose pentaacetates were computed by using the MO-LCAO method of Del Re for σ-charges and the Huckel MO method for π-charges. The potential and free energies of sixteen aldohexopyranose pentaacetates in the C1( D ) and 1C( D ) conformations were estimated. Minimization of the energies of these conformations was studied by suitably tilting the axial Cue5f8C and Cue5f8O bonds. As with the free sugars, considerable release of strain is achieved when tilts of 4.5 and 2° are given to the axial CH2OAc and the axial OAc groups, respectively, involved in the Hassel—Ottar effect in the 1C( D ) conformations. In the case of C1( D ) conformations, the ideal models have the minimum energy even when the acetate groups are involved in syn-axial interactions, indicating that strain induced by axial acetate groups is less than that of axial hydroxyl groups. The calculated free-energies agree well with the experimental values after adding a value of 0.9 kcal.mole-1 for the anomeric effect of the acetoxyl group. The free-energy calculations also predict that α- D -idohexopyranose pentaacetate and α- D -altrose pentaacetate favour the C1( D ) conformation and β- D -idose pentaacetate a C1⇄1C equilibrium in solution, in agreement with n.m.r. studies.

Theoretical investigation of the structures of H2SO4, (CH30)2SO2 and CH30S03-

Abstract The energies of the various conformers formed by rotating around the Sue5f8-O bond in H 2 SO 4 , (CH 3 O) 2 SO 2 and CH 3 OSO 3 - have been determined by ab initio molecular orbital methods using minimal (STO-3G) and extended (4-31G) basis sets. The (90°, 90°) conformation in H 2 SO 4 has been found to be the most stable, in agreement with the microwave spectral data for gaseous sulfuric acid. Calculations on dimethyl sulfate indicate that geometry optimization can dramatically alter the relative energies of the conformational isomers. Thus, after ROue5f8Sue5f8OR bond angle optimization, the energy difference between the (75°, 75°), (75°, 180°) and (180°, 180°) conformations is only about 0.21 kcal mol -1 suggesting that all three rotational isomers are likely to occur. This explains the detection of different conformers of dimethyl sulfate by different experimental techniques. The barrier to rotation around the Sue5f8O bond in the CH 3 OSO 3 t system is calculated to be very small, 1.2 kcal mol -1 . A comparison of these species with related anomeric systems is presented and the nature of the interactions of polar bonds in determining the preferred conformation is discussed.

Computer modelling studies of ribonuclease A-pyrimidine nucleotide complexes

Different modes of binding of pyrimidine monophosphates 2-UMP, 3-UMP, 2-CMP and 3-CMP to ribonuclease (RNase) A are studied by energy minimization in torsion angle and subsequently in Cartesian coordinate space. The results are analysed in the light of primary binding sites. The hydrogen bonding pattern brings out roles for amino acids such as Asn44 and Ser123 apart from the well known active site residues viz., His12,Lys41,Thr45 and His119. Amino acid segments 43-45 and 119-121 seem to be guiding the ligand binding by forming a pocket. Many of the active site charged residues display considerable movement upon nucleotide binding.

Anomeric effect in carbohydrates-an ab initio study on extended model systems

The anomeric effect is studied at theab initio Hartree-Fock level using extended model systems. This has enabled us to study the effect of substitution on the anomeric effect and the Δ2-effect in greater detail. An attempt is made to compare the results with available experimental data.

Acyclic sugars: the ring-opening of 2-acetamido-2-deoxyhexopyranoses in trifluoroacetic acid

During an investigation of solvent effects on the anomeric equilibria of 2-acetomido-2-deoxyhexoses, we have observed a novel, reversible reaction of these sugars with trifluoroacetic acid that is described herein. Fig. 1 shows the H-n.m.r. spectra of 2-acetoamido-2 deoxy-D-glucopyranose (1) in trifluoroacetic acid, recorded at intervals after dissolution. A sharp doublet (J = 5.5 Hz) at delta = 7 and a singlet at delta = 2.6 begin to appear within a few min. The increase in the intensity of these resonances is accompanied by a concomitant decrease of the H-1 peak at delta = 5.4 and the methyl resonance at delta 2.4 of 1. The reaction is essentially complete after 3 h, and Fig. 1c shows the spectrum after 19 h. During this conversion, the specific rotation changes from initial alpha D of +49 deg. to a final value of –54.4 deg. Evaporation of the trifluoroacetic acid in vacuo yielded an unstable oil that showed the presence of acetamido and trifluoroacetyl groups (Vco 1680 1795 cm-1). Addition of D2O led to rapid reversal of the reaction. Fig. 2 shows the n.m.r spectra of the oil in D2O, recorded at intervals. The doublet at delta 7 and the singlet at delta 2.6 disappear, whereas the resonances of 1 reappear. An interesting feature of the reverse reaction is the growth and decay of doublet at delta = 6.5 and a methyl resonance at delta 2.15, characteristic of a short-lived intermediate. Analysis of curves of the progress of reaction suggests that consecutive first-order processes are operative.