摘要:

Solvent effects on a number of different processes have been surveyed, and results of the application of multiple linear regression analysis are discussed. The processes examined include examples of solubility of gases or vapours, distribution coefficients of solutes between water and a series of solvents, and solvent effects on conformational equilibria, on keto–enol tautomerism, and on reaction rates. It is shown that two particular equations, that due to Koppel and Palm and extended by Makitra and Pirig, and that due to Abraham, Kamlet, and Taft, can cope quite satisfactorily with solvent effects on these various processes. It is pointed out that interpretation of parameters obtained from equations that involve macroscopic quantities such as ΔG≠or ΔG0is not necessarily straightforward, and that some model is needed in order to interpret these macroscopic quantities in terms of microscopic quantities that can characterise, for example, solute–solvent interactions.

ISSN:0008-4042    

DOI:10.1139/v88-420

出版商:NRC Research Press    

年代:1988

数据来源: NRC

摘要:

Allinger's MMP2(85) program has been converted to an IBM environment, and the dimensions expanded to a current maximum of 999 atoms. Substantial additional expansion will be possible. An all-atom set of parameters, which permit Allinger's comprehensive force field to be applied to the molecular mechanics treatment of peptides, has been determined. These parameters, termed MMPEP, contain 21 atom types: 5 for carbon, 6 for hydrogen, 5 for nitrogen, 4 for oxygen, and 1 for sulfur, and are based on crystallographic heavy atom bond lengths and bond angles, vibrational and microwave spectra, andabinitiocalculations. To minimize the conformational energy of a peptide from an initial starting geometry, all internally stored parameters are released, and replaced by PEPCON, a 360-line external file containing the MMPEP parameters.The ability of the MMPEP parameterization of MM85 to reproduce experimental crystal structures has been tested on several peptides and polypeptides, and the use of a dielectric constant ϵ = 78.5 D leads to the following results: Ala-Ala-Gly (rms = 0.261); Gly-Gly-Val (rms = 0.349); glutathione (rms = 0.417); crambin (327 heavy atoms; rms = 0.310 for all heavy atoms); insulin (389 heavy atoms; rms = 0.646 for all heavy atoms); the origins of deviations can be interpreted. No problems have been encountered in the application of the Newton–Raphson minimization procedure to such large molecules as crambin and insulin, even though all possible nonbonded interactions have been retained. On the IBM 3081 computer, real time minimization of trip)eptides requires 1–2 min, crambin requires 250 min, and insulin 200 min. Since hydrogen bonding in Allinger's force field is a natural result of electrostatic and van der Waals interactions, in MMPEP hydrogen bonding is taken into account through the large number of hydrogen atom types and their different bond moments and van der Waals radii.

ISSN:0008-4042    

DOI:10.1139/v88-421

出版商:NRC Research Press    

年代:1988

数据来源: NRC

摘要:

Scheraga's ECEPP program has been used to determine the relationship between one-point energies and the energies minimized by a quadratic procedure, for different sizeddihedral angle grid searches of simple peptides. Based on these trials, a new subroutine, INIT, has been written and incorporated into the program. This subroutine calculates the one-point ECEPP energies of up to 200,000 random permutations of, 180 and (χ1) = −60, 180 with all ω = χ≠1 = 180; after each 40,000 permutations, the structures having the 10 lowest energies are ordered and selected for minimization. The ECEPP program has been modified further to provide an MMP2(85) input file as part of its normal output. This allows structures located by INIT to be minimized automatically, and then refined by the Newton–Raphson minimization and MMPEP parameters of MMP2(85).During the development of this protocol, it has been found that MMPEP correctly reproduces theC7conformational preference of the alanyl dipeptide in nonpolar media, and also the experimentally observed shift to αRandPIIconformations in polar solvents, when the dielectric constant ϵ = 78.5 D. This dielectric constant has, therefore, been selected for a conformational analysis, using INIT/MMPEP, of the peptides Gly-Trp-Met-Asp-Phe-NH2(GLMAP), Gly-D-Trp-Met-Asp-Phe-NH2(GDMAP), and Gly-Gly-Met-Asp-Phe-NH2(GGMAP); GLMAP is CCK-5, a cholecystokinin fragment possessing anticonvulsant activity, which is found in the brain. The analogs GDMAP and GGMAP are not active, or much less so than GLMAP. One strongly preferred structure has been found, in each case, for GLMAP (GLMAP3) and GDMAP (GDMAP39). These structures are very similar, in the nature of the edge-to-face stacking of their Trp and Phe aromatic rings, but the C-terminal regions differ. The conformation of the C-terminal tetrapeptide of GLMAP3 is identical to a previously calculated structure of CCK-4. A comparison of the C-terminal regions of GLMAP3 and GDMAP39 with the structure of 5,5-diphenylhydantoin suggests that the mechanisms of anticonvulsant action of phenytoin and CCK-5 are not the same. In the absence of an aromatic–aromatic interaction, no clear-cut conformational preference is found for GGMAP. The structure of GGMAP whose C-terminal region is the same as that of GLMAP3 (GGMAP20) is 1.51 kcal/mol higher in energy than the lowest energy structure, and lacks the hydrophobic wall provided by the Trp residue of GLMAP3.

ISSN:0008-4042    

DOI:10.1139/v88-422

出版商:NRC Research Press    

年代:1988

数据来源: NRC

摘要:

A set of parameters, termed MMPEN, has been determined for the bicyclic nucleus of penicillin, which, in conjunction with the appropriate parameters from MMPEP and the internally stored parameters of the program, allow Allinger's force field and MMP2(85) program to be applied to the molecular mechanics treatment of penicillins. The MMPEN parameters are based on crystallographic heavy atom bond lengths and bond angles, vibrational spectra, and molecular orbital calculations. The parameters reproduce the experimental crystal structures of several penicillins, including penicillin G and penicillin V, with an average deviation of 0.005 Å in bond lengths, 0.5° in bond angles, and 3° in dihedral angles. Conformational analyses of penicillin G and penicillin V, for a dielectric constant, ϵ = 78.5 D suggest that neither penicillin retains the crystal structure in solution. In both cases, the global minima have the C3-carboxyl group antiperiplanar to the 2β-methyl group in the thiazolidine ring, and the side chains are oriented so that the amide N-H occupies the convex face of the molecule. The predicted conformations of the methyl esters of penicillin G and bisnorpenicillin G, for a dielectric constant of 4.8 D, are consistent with the nuclear magnetic resonance spectra obtained for these compounds in chloroform solvent.

ISSN:0008-4042    

DOI:10.1139/v88-423

出版商:NRC Research Press    

年代:1988

数据来源: NRC

摘要:

Using the MMPEN parameters of Allinger's MMP2(85) force field, a conformational analysis has been performed on four biologically active penicillins;D-ampicillin,L-α-phenoxyethylpenicillin, penicillin G, and penicillin V, and on five biologically inactive or much less active penicillins:L-ampicillin,D-α-phenoxyethylpenicillin,N-methylpenicillin G, 6α-methylpenicillin G, and bisnorpenicillin G. Antibacterial activity is found to be associated with the existence of a global minimum having a compact structure, whose convex face is accessible to a penicillin binding protein (PBP), with the C3-carboxyl group and the side-chain N-H exposed on this face. Using the MMPEP parameters of MMP2(85), a conformational analysis has been performed on phenylacetyl-D-Ala-D-Ala-O−, a peptide model of the normal substrate of a PBP. Labischinski's global minimum has been reproduced, along with structures that correspond to Tipper and Strominger's proposal that the N4—C7 bond of a penicillin corresponds to the Ala–Ala peptide bond, and to Hasan's proposal that the N4—C5 bond of penicillin corresponds to the peptide bond. For both models, conformations of the peptide related to the pseudoaxial and pseudoequatorial conformations of the thiazolidine ring of penicillin G have been examined. It is concluded that penicillin is not a structural analog of the global minimum of the peptide; however, comparisons based on unbound conformations of PBP substrates are unable to determine which model is more appropriate, or which conformation of penicillin G is the biologically significant one. Using the ECEPP/MMPEP strategy, a model of the active site of a PBP has been obtained, following a search of 200,000 structures of the peptide Ac-NH-Val-Gly-Ser-Val-Thr-Lys-NH-Me. This peptide contains the sequence at the active site of a PBP ofStreptomycesR61, for which it is also known that the C3-carboxyl group of penicillin binds to the ϵ-amino group of lysine, and the β-lactam reacts chemically with the serine OH. The lysine and serine side chains and the C-terminal carbonyl group are found to occupy the concave face of the active site model.A strategy for the docking of penicillins or peptides to this model, with full minimization of the conformational energies of the complexes, has been devised. All active penicillins bind through strong hydrogen bonds to the C3-carboxyl group and the side-chain N-H, and with a four-centered relationship between the O-H of serine and the (O)C-N of the β-lactam ring. The geometrical parameters of this relationship are reminiscent of those found in thegasphasetransition state ofneutralhydration of a carbonyl group. When the energies of formation and geometries of the pseudoaxial and pseudoequatorial penicillin G complexes are examined, there is now a clear preference for the binding of thepseudoaxialconformation, which is the global minimum of the uncomplexed penicillin in this case. A similar examination of the peptide complexes reveals that only the conformation of the peptide that corresponds to Tipper and Strominger's model, and is based on the pseudoaxial conformation of penicillin G, can form a complex with a geometry and energy comparable to those of a biologically active penicillin.

ISSN:0008-4042    

DOI:10.1139/v88-424

出版商:NRC Research Press    

年代:1988

数据来源: NRC

摘要:

5,5-Diphenylhydanytoin (phenytoin) is the most widely used anticonvulsant drug, but has many side effects. Although its chemical mode of action is unknown, phenytoin is believed to function primarily by interference with the transport of sodium ions across the neuronal membrane. Structure–activity and lipophilicity–activity studies suggest that the drug interacts with its receptor through hydrogen bonding to the N3—C4 amide bond, and an aromatic–aromatic interaction with the C5 substituent. Since sodium channels are cysteine-rich peptides, whose function depends upon the cysteinecystine redox process, it has been hypothesized that the action of the phenytoin receptor may be mimicked by a properly designed cyclodepsipeptide containing a cystinyl moiety, a cavity lined with five oxygen atoms oriented in the trigonal-bipyramidal manner appropriate for selective transport of sodium ions, and a site for the binding of phenytoin. A computer programme and strategy were developed to permit the three-dimensional structures of potential target molecules to be viewed, prior to synthesis. Use of this programme led to the discovery of Boc-L-cystinyl-glycyl-L-prolyl-glycyl-L-prolyl-L-cystine-OCHPh2. This compound, termed phenceptin, was synthesized from a linear precursor containingtert-butoxycarbonyl protection at the N-terminus, benzhydryl ester protection at the C-terminus, and trityl protection at sulfur. Detritylation and cyclization to phenceptin were accomplished with iodine in methanol–pyridine. Using ann-octanol membrane to study the kinetics of ion transport, phenceptin was found to transport sodium ions selectively, but only in its oxidized, cyclic form. This transport was inhibited significantly by one mol-equiv. of phenytoin, and not at all by biologically inactive analogs of the drug. The nature of the binding of phenytoin to phenceptin was examined by nuclear magnetic resonance, inn-C8D17-OH solvent, and found to involve hydrogen bonding of the drug to a glycine residue whose oxygen atom is involved in complexation to sodium ions.

ISSN:0008-4042    

DOI:10.1139/v88-425

出版商:NRC Research Press    

年代:1988

数据来源: NRC

摘要:

Proton nmr line-broadening experiments at ambient and elevated (to 215 MPa) pressures show that the rate of electron transfer between Fe(phen)32+and Fe(phen)33+as bisulfates in D2O/D2SO4is represented by the activation parameters (at ionic strengthI ~ 0.4 mol kg−1) ΔH≠ = 1.6 ± 0.5 kJ mol−1, ΔS≠ = −102.2 ± 1.6 JK−1mol−1,k(276 K) = 1.31 × 107 kg mol−1s−1, and (atI ~ 0.3 mol kg−1and a mean pressure of 100 MPa) ΔV≠ = −2.2 ± 0.1 cm3mol−1. For the same reaction of the perchlorate salts (total [Fe] 0.046–0.065 mol kg−1) in CD3CN, ΔH≠ = 11.0 ± 1.0 kJ mol−1, ΔS≠ = −72.5 ± 3.6 J K−1mol−1,k(277 K) = 8.0 × 106 kgmol−1s−1, and ΔV≠ = −5.9 ± 0.5 cm3mol−1. For water as solvent, ΔV≠is satisfactorily accounted for by a classical theory of the Stranks–Hush–Marcus type. Volumes of activation for electron self-exchange are shown to provide criteria for non-adiabaticity and for dominance of (non-aqueous) solvent reorganization dynamics; on this basis, it is seen that neither of these factors is important in the title reactions.

ISSN:0008-4042    

DOI:10.1139/v88-426

出版商:NRC Research Press    

年代:1988

数据来源: NRC

摘要:

We study the compatibility between the linearized phenomenological equations of an homogeneous chemical gaseous system, and the theoretical ones obtained with the aid of the kinetic theory of gases. Our discussion is based on the concept of chemical relaxation mode. The theoretical description is provided by a reactive Boltzmann equation for each component of the system. Then, we show the conditions under which the linearized phenomenological equations can be reproduced.

ISSN:0008-4042    

DOI:10.1139/v88-427

出版商:NRC Research Press    

年代:1988

数据来源: NRC

摘要:

A galactomannan and a branched (1 → 3)-β-D-glucan were isolated from the water hyacinth plant. The galactomannan, purified from the cold water extract, is composed ofD-galactose andD-mannose in a ratio of 1.0:2.8. It has a (1 → 4)-linkedD-mannose backbone, one out of threeD-mannose residues being substituted with a single α-D-galactosyl unit. The branched (1 → 3)-β-D-glucan isolated from the hot water extract has a main chain composed of β-(1 → 3)-linkedD-glucopyranosyl residues, and two single β(1 → 6)-D-glucopyranosyl groups attached as side chains to, on average, every 5 sugar units of the main chain. In addition, the branching of the β-glucan occurs regularly at O-6 of the β-(1 → 3)-linked backbone.

ISSN:0008-4042    

DOI:10.1139/v88-428

出版商:NRC Research Press    

年代:1988

数据来源: NRC

摘要:

The stereochemical assignment aserythroandthreofor two pairs of 2-(aryloxy)-1-(2-piperidyl)ethanols1and2is described. Their CHO–CHN coupling constants were measured on the phase sensitive1H–1H homocorrelation spectra (DQF–COSY), optimized by means of the LAOCOON-3 program, and compared with the calculated values from an MM2 conformational analysis. The experimental constants wereJerythro = 3.3/3.8 Hz andJthreo = 6.4/6.8 Hz, whereas the calculated values were 2.5 and 5.4 Hz, respectively.13C nuclear magnetic resonance steric shielding of the C(3) carbon atom in theerythrodiastereomers confirms the results of the conformational analysis.

ISSN:0008-4042    

DOI:10.1139/v88-429

出版商:NRC Research Press    

年代:1988

数据来源: NRC