Biomedical subjects

A Liwo

Publications and source records attributed to A Liwo.

42 records · Page 3Linked to original sources

PubMed1991

Conformational analysis of [Cpp1, Sar7, Arg8] vasopressin by 1H-NMR spectroscopy and molecular mechanics calculations.

A combined 1H-NMR and molecular mechanics study of [Cpp1, Sar7]AVP was performed in order to select the most probable conformations in DMSO solutions. The NMR constraints obtained were employed in the selection of starting conformations of the cyclic moiety of the analog. In particular, the diminished accessibility of the Asn5 NH proton to solvent and the close contact between Cpp1 and Cys6 C alpha H protons suggests a beta-turn conformation at the Phe3-Gln4 residues. Energy minimization was carried out both in the ECEPP/2 (rigid-valence geometry) and in the AMBER (flexible-valence geometry) force fields. Comparison of the experimental and calculated values of NMR characteristics has revealed that conformations containing type I, II, and III beta-turns at the Phe3-Gln4 residues are in reasonable agreement with the experimental data, with a dynamic equilibrium between the beta I (beta III) and beta II type structures of the cyclic part being the most probable. All of these conformations prefer the negative chirality of the disulfide bridge (theta 3 approximately -90 degrees). Five representative conformations were chosen for the acyclic tail: one with a beta I, one with a beta II'-turn at the Sar7-Arg8 residues, two extended-type conformations, and a conformation with a gamma-turn at Sar7. Because only high-energy extended conformations were in agreement with NMR data, it was concluded that the acyclic tail has considerable conformational flexibility in solution. The conformations obtained are discussed in terms of the structure-function relationship of the neurohypophyseal hormone analogs.

Amino Acid Sequence↗

PubMed1991

Molecular determinants of singlet oxygen binding by anthraquinones in relation to their redox cycling activity.

A series of model anthraquinones with varying symmetry of pi-electron density distribution have been examined to verify our previous hypothesis concerning the essential role of quinone-singlet oxygen complex formation by asymmetric anthraquinones in their peroxidating properties. Comparison of the results of enzymatic studies using NADH dehydrogenase with those of cyclovoltammetric measurements fully confirmed the assumption that one-electron transfer mediation is facilitated by the preceding quinone-oxygen complex formation. To extend the scope of the molecular determinants of oxygen binding found in our previous studies, CNDO/2 and molecular electrostatic field (MEF) calculations have been performed. It has been concluded that the analysis of molecular electrostatic field as well as the dipole moment components has to be taken into account to judge whether a mutual orientation of the quinone and oxygen molecule can be reached which enables binding to occur. The second important factor is the appropriate symmetry of the quinone outer filled orbitals which assures that binding is not forbidden by the Woodward-Hoffman rules. These characteristics also explain the lack of oxygen binding by some asymmetric anthraquinones. The efficient electron transfer mediation be anthraquinones requires, beside the formation of the intermediate quinone-oxygen complex, effective catalysis of this process by oxidoreductase enzyme. The results obtained with model anthraquinones indicated that compounds with more than one phenolic group and an unsubstituted quinone carbonyl are good NADH dehydrogenase substrates. Imino derivatives and compounds with a reduced number or without free phenolic groups exhibit low affinity towards the enzyme.

Anthraquinones↗

PubMed1989

A theoretical study of glucosamine synthase. Part I. Molecular mechanics calculations on substrate binding.

Glucosamine synthase transfers the gamma-amino group of glutamine to fructose, producing 1-glucosamine which is the key constituent of bacterial and fungal cell walls. In this study, model calculations were performed on substrate binding to the enzyme active site. Two models of the active site of glucosamine synthase were proposed, which assume two different sequences of aminoacids, Cys-Gly-Ile and Cys-Ala-Cys, the first one being the N-terminal sequence of the Escherichia coli enzyme. Several initial geometries were assumed for these tripeptides, the energy was then optimized by means of molecular mechanics. It has been found that the structure which is both energy optimal and satisfies the assumed cysteine sulphur arrangement consists of combinations of C7eq and C7ax conformations of single residues. Molecular mechanics calculations were then performed on glutamine and D-fructose-6-phosphate, which are the substrates of the enzymatic catalysis, and on their complex with the enzyme glutamine-binding site. The spatial configuration of the compounds under study, which is optimal as far as the reaction path is concerned, also turned out to be an energy minimum.

Alanine↗

PubMed1989

Molecular mechanics calculations on deaminooxytocin and on deamino-arginine-vasopressin and its analogues.

The backbone conformations of the cyclic moieties of 1-[beta-mercaptopropionic acid]-oxytocin [( Mpa1]-OT), [1-beta-mercaptopropionic acid]-arginine-vasopressin [( Mpa1]-AVP), [1-(beta'-mercapto-beta,beta-cyclopentamethylene)propionic acid]-arginine-vasopressin [( Cpp1]-AVP), and [1-thiosalicylic acid]-arginine-vasopressin [( Ths1]-AVP) have been analyzed by means of molecular mechanics. In these calculations, the side chains were simulated by pseudoatoms. For the three last compounds, the calculations were also performed on the whole molecules, in order to shed light on the differences in their biological activity. Their starting conformations were obtained by attaching the acyclic tail and side chains to the lowest energy conformations of the cyclic parts. In the case of [Ths1]-AVP, however, other starting conformations were also examined, which were obtained by attaching the planar benzene ring to the lowest energy conformations of [Mpa1]-AVP. In the calculations, all the degrees of freedom were relaxed and Weiner's force field was used, the parameters required for the benzene parts of [Ths1]-AVP being determined from the experimental data available, as well as from the results of molecular dynamics calculations on the model compounds. The lowest energy conformations of [Mpa1]-AVP and [Cpp1]-AVP are similar, while [Ths1]-AVP differs from them near the disulphide region, due to the presence of a planar benzene ring. Interactions involving the charged guanidine group of arginine make, in each case, an important contribution to the conformational energy. A model description of the shapes of the oxytocin and vasopressin ring has been proposed, which is based on the cyclohexane geometry. This description is in good correlation with the energetics of the conformations corresponding to different shapes.

Algorithms↗

PubMed1989

Theoretical studies of the mechanism of the action of the neurohypophyseal hormones. I. Molecular electrostatic potential (MEP) and molecular electrostatic field (MEF) maps of some vasopressin analogues.

Continuing our theoretical studies of the oxytocin and vasopressin analogues, we have analysed the molecular electrostatic potential (MEP) and the norm of the molecular electrostatic field (MEF) of [1-beta-mercaptopropionic acid]-arginine-vasopressin ([ Mpa1]-AVP), [1-(beta-mercapto-beta,beta-cyclopentamethylene)propionic acid]-arginine-vasopressin ([Cpp']-AVP), and [1-thiosalicylic acid]-arginine-vasopressin ([Ths']-AVP) whose low-energy conformations were calculated in our previous work. These compounds are known from experiment to exhibit different biological activity. The scalar fields mentioned determine the energy of interaction with either charged (MEP) or polar (MEF) species, the energy being in the second case either optimal or Boltzmann-averaged over all the possible orientations of the dipole moment versus the electrostatic field. The electrostatic interactions slowly vanish with distance and can therefore be considered to be the factor determining the molecular shape at greater distances, which can help in both predicting the interactions with the receptor at the stage of remote recognition and in finding the preferred directions of solvation by a polar solvent. In the analysis of the fields three techniques have been used: (i) the construction of maps in certain planes; (ii) the construction of maps on spheres centered in the charge center of the molecule under study and of poles chosen according to the main axes of the quadrupole moment; and (iii) the construction of surfaces corresponding to a given value of potential. The results obtained show that the shapes of both MEP and MEF are similar in the case of [Mpa1]-AVP and [Cpp1]-AVP (biologically active), while some differences emerge when comparing these compounds with [Ths1]-AVP (inactive). It has also been found that both MEP and MEF depend even more strongly on conformation.

Electrochemistry↗

PubMedDate not supplied

Conformational aspects of differences in requirements for oxytocin and vasopressin receptors.

Conformational energy calculations were carried out on three non-peptide antagonists of oxytocin and vasopressin: penicilide (compound 1; selective for oxytocin receptors), 1-¿1-[4-(3-acetylaminopropoxy(benzoyl]-4-piperidyl¿-3,4-dihydro-2( 1H)-quinoline (compound 2; selective for vasopressin V1 receptors) and 5-dimethylamino-1-¿(2-methylbenzylamino)-benzoyl¿-2,3,4,5-tetrahyd ro-1H-benzapine (compound 3; selective for vasopressin V2 receptors). The obtained low-energy conformations of compound 1 were compared with low-energy conformations of oxytocin (OT) and low-energy conformations of compounds 2 and 3 were compared with low-energy conformations of arginine vasopressin (AVP). It was found that the affinity of the non-peptide antagonists and their selectivity for vasopressin and oxytocin receptors is probably connected with mimicking the aromatic rings of the Tyr2 and the Phe3 residues of AVP in the case of compounds 2 and 3 and with mimicking the Tyr2 residue and the Ile3 or Leu8 residues of OT by the outer benzene ring and the isobutyl group of compound 1. Application of the results in the design of more potent non-peptide antagonists of OT and VP is also discussed.

Antidiuretic Hormone Receptor Antagonists↗