Conformation-dependent potential

Gaillard, P. Carrupt, P.-A. Testa, B., The conformation-dependent lipophilicity of morphine glucuronides as calculated from the molecular lipophilicity potential, Bioorg. Med. Chem. Lett. 4, 737-742 (1994). 

Momany, F. A., V. J. Klimkowski, and L. Schafer. 1990. On the Use of Conformationally Dependent Geometry Trends from Ab Initio Dipeptide Studies to Refine Potentials for the Empirical Force Field CHARMM. J. Comp. Chem. 11, 654-662. 

The prime objective of this concise review is to provide an illustration of the interaction of these two disciplines using particular examples. In choosing the examples, we seek to demonstrate the potentialities of the conformation-dependent design of the sequences of monomeric units in heteropolymer macromolecules. Under such a design, their chemical structure is controlled not only by the kinetic parameters of a reaction system but also by the conformational statistics of polymer chains. 

Another consequence of the stronger interactions upon ionization is that the equilibrium geometry of the ionized complex may differ signihcantly from that of the neutral states. Broadened ionization onsets are frequently attributed to the spectral superposition of ionization into several vibrational levels for which Franck-Condon factors are more favorable. As a result, the adiabatic ionization potential may be considerably lower than the vertical potential, and the observed ionization onsets may occur above the adiabatic potential. Another factor to be considered is the conformation-dependent efifect, due to the different conformations of the solvent molecules. The most populated form of a complex may involve a less stable form of the solvent. After photoionisation, the lowest-energy dissociation channel in the complex ion leads to the most stable form of isolated solvent, which has to be taken into account for the estimate of the binding energy. 

In relation to the above it is obvious that passage of the pulmonary epithelium may depend on characteristics of a drug molecule. Not only the size, but also its solubility, overall charge, structural conformation and potential aggregation can have a significant effect on the absorption rate and bioavailabUity of the drug after pulmonary deposition. 

Molecular lipophilicity potential (MLP) has been developed as a tool in 3D-QSAR, for the visualization of lipophilicity distribution on a molecular surface and as an additional field in CoMFA studies [49]. MLP can also be used to estimate conformation-dependent log P values. 

Key Words 3D-QSAR hydrophobicity lipophilicity 3D-LogP conformation-dependent lipophilicity alignment-independent 3D descriptor molecular lipophilicity potential (MLP) ADME-related descriptor. 

W. Fickett in "Detonation Properties of Condensed Explosives Calculated with an Equation of State Based on Intermole-cular Potentials , LosAlamosScientific-LabRept LA-2712(1962), pp 38-42, reports that pseudopotential theories are obtd by an approach completely different from perturbation theories. The problem of defining a system of detonation products consisting of both solid carbon in some form and a fluid mixt of the remaining product species has been formally rearranged to a single fictitious substance with an extremely complicated compn- temp-dependent potential function , called the pseudopotential. The fictitious substance corresponding to this potential is clearly non-conformal with the components of the mixt... 

Contrary to the experimental electron density, the electrostatic potential is conformation dependent. Figure 18 shows the ORTEP view of /-butylCOproline-histidine-methylamide (tbuCOprohisNHMe) [55] which exhibit a folded conformation due to an intramolecular hydrogen bond (P-tum) between 0 and N3H (N3—O, = 2.935 A) as a consequence, hydrogen bond occurs between the histidine N4 and the N2 hydrogen (N4—N2 = 3.205 A). The effect of the pturn on the electron density has been discussed in refs. 28 and 64. 

Rigid Molecule Group theory will be given in the main part of this paper. For example, synunetry adapted potential energy function for internal molecular large amplitude motions will be deduced. Symmetry eigenvectors which factorize the Hamiltonian matrix in boxes will be derived. In the last section, applications to problems of physical interest will be forwarded. For example, conformational dependencies of molecular parameters as a function of temperature will be determined. Selection rules, as wdl as, torsional far infrared spectrum band structure calculations will be predicted. Finally, the torsional band structures of electronic spectra of flexible molecules will be presented. 

T. R. Stouch and D. E. Williams, J. Comput. Chem., 13, 622 (1992). Conformational Dependence of Electrostatic Potential Derived Charges of a Lipid Headgroup Glycerylphosphorylcholine. 

Among the -+ quantum-chemical descriptors, descriptors of different kinds of conformational dependence can be found - ionization potential, - electron affinity, molecular orbital energies are often LCD- or ICD-descriptors, while molecular energies are usually HCD-descriptors. 

Gaillard, R, Carrupt, P.-A. and Testa, B. (1994a). The Conformation-Dependent Lipophilicity of Morphine Glucuronides as Calculated from their Molecular Lipophilicity Potential. Bioorg. Med.Chem.Lett., 4,737-742. 

To take into account the effect of wrapping on dielectric-dependent pairwise interactions and assess its role in defining cooperativity, we have adopted a semiem-pirical procedure to algorithmically keep track of the conformation-dependent microenvironments. Thus, the in-bulk potential energy contributions are regarded as zero-order terms, while cooperative effects arise due to the wrapping of favorable interactions brought about by hydrophobic third-body participation (cf. Fig. 3.2c). 

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