Posters B Structure and Dynamics of Biomolecules B05-156 Spatial structure of substance P, neurokinin A and neurokinin B, determined by theoretical conformational analysis and quantum-chemical calculations methods. G.A.Agaeva Molecular Biophysics Laboratory, Department of Physics, Baku State University Baku, 370148, Azerbaijan, tel: 99412390523, fax: 99412983376, e-mail: [email protected] Three main mammalian tachykinin neuropeptides, substance P, neurokinin A and neurokinin B, are the agonists at the distinct molecularly characterized receptor types, called neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3) respectively. These neuropeptides are found in a wide range of tissues including the central and peripheral nervous system, salivary gland and gastro-intestinal tract. Substance P, neurokinin A and neurokinin B appear to be involved in many diverse biological processes such as smooth muscle contraction, blood pressure regulation, neurogenic inflammation, vasodilatation, salivation, pain transmission and etc. Antagonists of these neuropeptides can therefore perhaps be used as analgesics or anti-inflammatory compounds. To gain insight in their molecular mechanism of action, the structure and conformational behaviour of peptides and its analogs is studied in this thesis. Conformational studies of these neuropeptides aimed to interpret pharmacological structure-activity studies with respect to the substance P, neurokinin A and neurokinin B can be aided and validated by theoretical methods and results presented in this thesis. It may form the start of a more rational development of peptidomimetic ligands for therapeutically interesting targets. So in our work the spatial organization of three neurokinins – substance P, neurokinin A and neurokinin B have been investigated by theoretical conformational analysis methods and quantum-chemical calculations. For this a systematic conformational build-up procedure was used for undecapeptideamide substance P and two decapeptideamide- neurokinin A and neurokinin B. Calculation show that all lowest-energy conformations of these peptides have a common C-terminal pentapeptide with a single energetically preferred alpha-helical backbone conformation. All the peptides have similar sets of low-energy conformations and their spatial organization possible to describe by several families structures with identical C-terminal geptapeptides and different flexible conformers of the N-terminal parts. It was shown that N-terminus tetrapeptide sequence of substance P is capable to form beta- and gamma-turns, due to presence in chain of two prolins. But N-terminal parts of neurokinin A and neurokinin B energetically preferred forms an alpha-helical structure in stable conformational states. The conformational analysis of natural peptide and its analogues has allowed to define the most important specific contacts required for stabilizations of the spatial forms. For revealing the functionally important structured particularities of molecules were explored also conformational possibilities of biologically active and inactive glysine monosubstituted analogues of these peptides. The distributions of atomic charges for separate functional groups of peptides, as well as redistributions of atomic charges and changing the dipole moments as a result of monosubstitutions in amino acid sequence of natural peptides were determined by means quantum-chemical calculations. On the base of results conformational analysis of neurokinins and its glycine monosubstituted analogues was conducted searching an models of their antagonists or agonists with the minimumal amino acid sequence, containing all necessary functional groups, with secondary structure of native molecule, and with the conservation of general balance of charge. B05-157 Structural Insights into BAM-20P by Molecular Mechanics N.A.Akhmedov , Z.H.Tagiyev, E.M.Hasanov, G.A.Akverdieva Molecular Biophysics Laboratory, physics department, Baku State University, 370148, Baku, Z.Khalilov str. 23, tel: 39-03-05, E-mail: [email protected] The opioid dodecapeptid signed as BAM-20P was extracted from the medulla of bovine adrenal. This peptide play important role in the functioning of the central nervous system, because of that it is considered as neuropeptide. Apart from analgetic effect, BAM-20P shows other properties, as a substantiating, psychotropic action, a participation in a regulation of a visceral system of an organism, namely, exchange processes, a systems of digestion, a pancreas and cardiovascular system. The diversity of biological functions of given peptide is undoubtedly connected to its conformational possibilities. The conformational preferences of BAM-20P were analysed by molecular mechanics. The results of the research indicate that this molecule can exist in several stable states. The energy and geometrical parameters for such low-energy conformations are obtained. The high density of packaging of a polypeptide chain of the most preferential structures is accompanied by a installation of the numerous hydrogen bonds. In the majority of the low energy structures the side chains with aromatic rings have conformational mobility because of its localization on surface of the molecule. It is substantiated by physiological expediency: such mobility of these residues is probably necessary for complementary binding with the specific receptors and for the installation the hydrogen bonds with the solvent. In spite of presence of two clysine residues in the Tyr1-Met5 fragment of the molecule, corresponding to Met-enkephalin sequence, this part of peptide molecule is not labile, it has a turn of a chain with the residues Gly3 and Phe4 in a center of turn with the approaching of the atom groups NH Met5 and CO Gly2 . These results are in accordance with the available data of the experimental and theoretical investigations of Met-enkephalin, which introduse such structure with β-turn as predominant. It is possible to suppose, that exactly the indicated turn of a chain is a major factor in charge of opiate activity as in Met-enkephalin, so in BAM-20P and related peptides. The knowledge of the active conformations of a given peptide is a major step towards understanding its biological functions. The received data also will allow to plan the production of pseudoanalogs of BAM-20P with modified properties useful in therapy and medical diagnostic. B05-158 Molecular Mechanics Study of [D-ARG2]-Dermorphin Tetrapeptide Aanalogs G.A .Akverdieva. Molecular Biophysics Laboratory, physics department, Baku State University, 370148, Baku,Str.Z.Khalilov 23, Azerbaijan, 39-03-05, E-mail: [email protected] Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) is a potent and highly µ − selective opiod peptide, isolated from amphibian skin. It has the highest peripheral and central opiod-like activity. The structure-pharmacological activity relationship studies of this peptide have demonstrate the potent and prolonged antinociceptive activity of its D-Arg2 substituited tetrapeptide analogs. The present study was aimed to reveal the stable states and the conformational peculiarities, which are important for the functional activity of the dermorphin tetrapeptide analogs H-Tyr-D-Arg-Phe-Gly-OH (I) and H-Tyr- DArg-Phe- β -Ala-OH (II). The conformational properties of the tetrapeptides I and II were studied by molecular mechanics methods. The geometrical and energy parameters of the preferential conformations for these tetrapeptides are determined. The calculation results were compared to the conformational properties of the N-terminal dermorphin fragment, which was studied earlier. It is revealed that for the tetrapeptides I and II the low-energy conformations of natural peptide fragment are realized selectively. It is established, that for each analog the backbone form of the N-terminal dipeptide fragment is quite definite. So, the tetrapeptides I and II adopt the conformations, having the folded and extended backbone forms of dipeptide segment Tyr1-D-Arg2, respectively. Apparently the bond between aminoacid residues in the first and second positions is stabil only in the mentioned low- energy conformations of the investigated analogs. The conformational analysis results are in according with the data of the biological researches, revealed that Tyr1-D-Arg2 bond is stabil against aminopeptidase of peptidases. These findings allow to understand a steady large antinociceptive activity of the D-Arg-substituted dermorphin tetrapeptides and may be useful in the design of a new synthetic peptides with prolonged opiod activity. B05-159 Conformational study of the proline-rich segment (7-19) of the osteocalcin. G.A.Agaeva, R.E.Aliev Department of Physics, Baku State University 370148, Baku, Azerbaijan Tel: 99412390523, fax: 99412983376, e-mail: [email protected] Designing the new protein functional compounds, as a result determinations to their spatial organizations by means of theoretical conformational methods, is an actual problem of the theoretical biophysics and pharmacology. Osteocalcin is a major noncollagenous matrix protein of bone, dentin, and cementum. It is considered to play roles in bone formation and remodeling. This protein is known as a biochemical marker of bone metabolism. For diagnostic medical treatment of some bone diseases are used also the proline-rich segment 7-19 (H-Gly-Ala-Pro-Val-Pro-Tyr-Pro-Asp-Pro-Leu-Glu-Pro- Arg-OH) of the osteocalcin as a biochemical marker of the bone formation. The presence of six proline residues in the sequence