Theoretical conformational analysis of brain peptides. beta-Melanocyte-stimulating hormone

Using a semi-empirical method, an a priori conformational analysis of the octadecapeptide beta-melanocyte-stimulating hormone (beta-MSH) was carried out. The spatial structure of beta-MSH can be described by eight low-energy conformations, yielded by combinations of the most stable states of the respective free fragments. Calculations produced the values of all dihedral angles of the backbones and side chains of these forms as well as intra- and inter-residue interaction energies.     

Theoretical conformational analysis of phospholipids bilayers

We present a computational approach describing the conformation of lipid molecules (1-2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC)) organized in bilayers. The classical semi-empirical method used in peptide conformational analysis has been extended successfully to lipids. The excellent agreement between our theoretical predictions and recent experimental data on the molecular organization of lipid bilayers suggests that the method could be a valuable tool in the lipid conformational analysis but also in the prediction of orientation and mode of insertion of amphiphilic molecules into the lipid bilayer.     

Synthesis and carbon-13 nuclear magnetic resonance spectra of Cyclo(D-leucyl-L-leucine) and Cyclo(L-leucyl-L-leucine)

Cyclo(D -Leu-L -Leu) and cyclo(L -Leu-L -Leu) were synthesized, and their carbon-13 nmr spectra at 65 MHz were examined in dimethylsulfoxide and trifluoroacetic acid solutions. The chemical shift data are consistent with a boat or “twisted” boat conformation of the diketopiperazine ring in both solvents. There was no indication of protonation of the cyclic dipeptides by trifluoroacetic acid. Attempts at polymerizing the cyclic dipeptides were unsuccessful.     

Theoretical conformational analysis of oxytocin molecule.

The total semi-empirical conformational analysis of the oxytocin molecule has been carried out. It has been revealed the two main types of stable structures of cyclic moiety backbone and the great lability of the tail. The optimal spacing of cyclic moiety side chains has been found for every backbone structure. The calculation results are in good agreement with the data of physico-chemical investigations. Among the set of stable molecule structures reported in the present study are structures with beta-turn conformation of the cyclic moiety backbone and without closer spacing of the cyclic moiety and the tail, as well as structures with closely spaced N- and C-terminal parts which, however, lack beta-turn in the cyclic moiety.     

Theoretical conformational analysis of methylamide N-acetyl-L-arginine]

The spatial structure of methylamide N-acetyl-L-argine was studied taking into account the non-valent and electrostati interactions, the torsion energy, and the distorsion of valency angles. Calculation of the favourable conformations of the molecule was carried out with the use of all the combinations of angles phi, psi, chi1 divided by chi4 as an intital approximation. These correspond to the low energy forms of the main chain and to the minima of the torsion potentials of the side chain. Conformational possibilities of arginine and lysine were compared. The calculated stable conformation of N-acetyl-L-arginine-methylamide are compared with the geometry of arginine residues in the proteins with known structure.     

Theoretical conformational analysis of doulble-stranded polynucleotides]

Calculations of intramolecular interaction energy of two-stranded helical homopolynucleotide in the function of nine conformational variables have been carried out by the method of atom-atom potential functions. Four of these variables determine mutual position of base pairs, other four--deoxiribose ring conformation and other one--orientation of this ring with respect to the base. For this purpose an algorythm connecting dependent variables with independent ones has been developed. The investigation of energy function has shown that in the space of conformational parameters there are two valleys, which correspond to A-and B-families of conformations. Experimentaly determined conformations of two-stranded helical polynucleotides are located along the bottoms of these valleys. Along the bottom of each valley the intramolecular interaction energy changes rather little when conformational parameters change within a wide range. The valleys are separated by an energetical barrier.     

Theoretical conformational analysis of methylamide of N-acetyl-L-lysine]

The spatial structure of the methylamide of N-acetyl-L-lysine has been analysed taking into account non-bonded and electrostatic interactions, torsional energy, bond angles distortion and hydrogen bonding. Conformational capacities of the backbone and mutual dependence of spatial structures of the backbone and the side chain was described by conformational maps obtained by energy minimisation, the dihedral angles and the bond angles of the side chain being varied for every phi, psi point. Every possible combination for phi, psi, x1-x5-angles was used corresponding to the stable form of the backbone and to torsion potential minima of the initial approximations in the calculation of preferred conformations of the molecule. Comparisons are made between stable forms of the methylamide of N-acetyl-L-lysine and Lys residues in proteins with known structure.     

The conformational analysis of peptides using fourier transform IR spectroscopy

Fourier transform infrared spectroscopy (FTIR) can be used for conformational analysis of peptides in a wide range of environments. Measurements can be performed in aqueous solution, organic solvents, detergent micelles as well as in phospholipid membranes. Information on the secondary structure of peptides can be derived from the analysis of the strong amide I band. Orientation of secondary structural elements within a lipid bilayer matrix can be determined by means of polarized attenuated total reflectance–FTIR spectroscopy. Hydrogen–deuterium exchange can be monitored by the analysis of the, amide II band. This review gives some example of peptide systems studied by FTIR spectroscopy. Studies on alamethicin and α-aminoisobutyric acid containing peptides have shown that FTIR spectroscopy is a sensitive tool for identifying 3₁₀-helical structures. Changes in the structure of the magainins upon interaction with charged lipids were detected using FTIR spectroscopy. Tachyplesin is an example of a β-sheet containing membrane active peptide. Polarized ir spectroscopy reveals that the antiparallel β-sheet structures of tachyplesin are oriented parallel to the membrane surface. Synthesis of peptides corresponding to functionally/structurally important regions of large proteins is becoming increasingly popular. FTIR spectroscopy has been used to analyze the structure of synthetic peptides corresponding to the ion-selective pore of the voltage-gated potassium channel. In biomembrane systems these peptides adopt a highly helical structure. Under conditions, where these peptides are aggregated the presence of some intermolecular β-sheet structure can also be detected. © 1994 John Wiley & Sons, Inc.     

Theoretical conformational analysis of tripeptides. N-acetyl-L-alanyl-L-alanyl-L-alanyl methylamide]

The minimization procedure has been used for calculation of the local minimum conformations of threepeptide--Ac-(L-Ala)3-NHMe without intramolecular H-bonds. The significant energy deviations from additivity found, arising with increase backbone length to three links, can be considered as the evidence for mutual dependence of conformational states of the neighbouring and terminal amino acid residues. It have been shown that stability of alpha-helix form for alanine threepeptide in contrary to corresponding dipeptide is noticeably higher due to stabilizing effect of dispersion interactions. The results of calculations are compared with the data on conformational distrubution of the threepeptide fragments in proteins with known three dimensional structure. The important role of the backbone interaction in protein chain have been marked.     

Theoretical analysis of competitive conformational transitions in torsionally stressed DNA

This paper presents a theoretical analysis of the conformation of a torsionally deformed segment of DNA containing two sites susceptible to stress-induced transitions in secondary structure. A mechanical analysis of the ensuing competitive behavior is developed and applied to several phenomena of possible biological relevance. First, a molecular lesion which disrupts base pairing without strand breakage (such as a pyrimidine dimer) is shown to provide an effective nucleation site for further stress-induced denaturation. A competition is established between strand separation at this lesion site and at the A + T-richest portion of the molecule. The relative importance of these two forms of melting is shown to depend upon the A + T-content of the sites involved, segment length, local environmental conditions and the magnitude of the imposed torsional deformation. A possible alternative mode of behavior of a stressed segment of DNA involves transitions from B-form to Z-form. The second application of this theory analyzes the interplay between B → Z transitions and local denaturation in torsionally stressed DNA. Finally, local melting is shown to be energetically preferred over transitions to A-form under physiologically reasonable conditions in vitro, due primarily to the greater degree of unwinding involved in melting.The mechanical theory presented here makes several simplifying assumptions regarding the nature of the transitions and the sequences involved. First, the theory is developed explicitly for the competition between two sites of possible transition, with no further consideration given to conformational degeneracy or sequence effects. These sites are regarded as being uniform in composition. A multistate, heteropolymeric statistical mechanical transition theory is required to account rigorously for degeneracy and the influence of base sequence. A preliminary formulation of such a theory is used to analyze the denaturation of a segment containing a site of disrupted base pairing.     

Optical rotatory properties of L-cystine conformational isomers. Theoretical analysis

The near ultraviolet chiroptical properties of L -cystine conformational isomers are examined on a static, “one-electron” model in which the disulfide moiety is the chromophoric group and the atoms of the L -alanyl fragments are treated as perturbers. The zeroth order chromophoric wave functions are calculated on a semiempirical molecular orbital model in which excited states are constructed in the virtual orbital-configuration interaction approximation. The perturbing environment is represented by point charges located at the atomic centers of the L -alanyl fragments. Chromophore–perturber interactions are expressed as charge–multipole moments with only the charge–dipole and charged–quadrupole terms being retained in the calculations. Vicinal contributions to the rotatory strengths of the five lowest energy disulfide transitions are computed for 30 conformational isomers of the L -cystine dizwitterion. The results provide support for the view that vicinal or peripheral effects can account entirely for the observed near ultraviolet (λ > 230 nm) chiroptical properties of L -cystine and its derivatives and that these properties are diagnostic of conformational features external to the disulfide moiety.     

Theoretical conformational analysis of a family of alpha-helical immunocytokines.

According to the results of the theoretical conformation analysis and available experimental data, the known immunocytokines can be divided into two groups: alpha-helical (IFNs-alpha, beta, gamma, omega; IL-2, 3, 4, 5, 6, 7; G-, M-, GM-CSFs; cMGF, PDGF) and beta-pleated proteins (ILs-1 alpha, beta; TNFS-alpha, beta). IFNs-alpha, beta, gamma, omega, IL-6, G-CSF, cMGF were shown to form a family of alpha-helical globular proteins characterized by a statistically significant homology in amino acid sequences and by common features of the secondary structure formation. Comparison of the sequences of 72 IFNs-alpha, beta, omega reveals three clusters of conservative amino acid positions. Their participation in the formation of active sites of IFN-alpha, beta, omega is supposed.     

Synthetic and conformational studies on dehydroalanine-containing model peptides

Three model dipeptides containing a dehydroalanine residue (delta Ala) at the C-terminal, Boc-X-delta Ala-NHCH3 [X = Ala, Val, and Phe,] have been synthesized and their solution conformations investigated by 1H-NMR, IR, and CD spectroscopy. NMR studies on these peptides in CDCl3 clearly indicate that the NH group of dehydroalanine is involved in an intramolecular hydrogen bond. This conclusion is supported by IR studies also. Nuclear Overhauser effect (NOE) studies are also accommodative of an inverse gamma-turn-type of conformation that is characterized by conformational angles of phi approximately -70 degrees and psi approximately +70 degrees around the X residue, and a C alpha i + 1 H-Ni + 2H interproton distance of 2.5 A. It appears that unlike dehydrophenylalanine or dehydroleucine, which tend to stabilize beta-turn type of structures occupying the i + 2 position of the turn, dehydroalanine favors the formation of an inverse gamma-turn, centered at the preceding L-residue in such solvents as CDCl3 and (CD3)2SO. A comparison of solution conformation of Boc Val-delta Ala-NHCH3 with the corresponding saturated analogue, Boc-Val-Ala-NHCH3, is also presented and shows that dehydroalanine is responsible for inducing the turn structure. It may be possible to design peptides with different preferred conformations using the suitable dehydroamino acid.