Conformational selection

Thermodynamically it would be expected that a ligand may not have identical affinity for both receptor conformations. This was an assumption in early formulations of conformational selection. For example, differential affinity for protein conformations was proposed for oxygen binding to hemoglobin [17] and for choline derivatives and nicotinic receptors [18]. Furthermore, assume that these conformations exist in an equilibrium defined by an allosteric constant L (defined as [Ra]/[R-i]) and that a ligand [A] has affinity for both conformations defined by equilibrium association constants Ka and aKa, respectively, for the inactive and active states ... 

Equation 1.9 indicates that if the ligand has an equal affinity for both the Ri and Ra states (a = 1) then Poo/po will equal unity and no change in the proportion of Ra will result from maximal ligand binding. However, if a > 1, then the presence of the conformationally selective ligand will cause the ratio Poo/Po to be > 1 and the Ra state will be enriched by presence of the ligand. 

A conformational selection model of prion transmission barriers 800... 

Thus, all results with cyclohexene oxides are compatible with a configurational and conformational selection by the enzyme, preferential attack at an (S)-configured C-atom, and Zrans-diaxial opening. 

The major hurdle to overcome in the development of 3D-QSAR models using steric, electrostatic, or lipophilic fields is related to both conformation selection and subsequent suitable overlay (alignment) of compounds. Therefore, it is of some interest to provide a conformation-ally sensitive lipophilicity descriptor that is alignment-independent. In this chapter we describe the derivation and parametrization of a new descriptor called 3D-LogP and demonstrate both its conformational sensitivity and its effectiveness in QSAR analysis. The 3D-LogP descriptor provides such a representation in the form of a rapidly computable description of the local lipophilicity at points on a user-defined molecular surface. 

The outstanding feature of the active transport is the selectivity of the complexation process, between K+ and Na. The enzyme is selective first to Na+ and then to K+ in its different conformations. Selectivity is governed by coulombic forces and differences in ionic radii. 

Every discussion of the Diels-Alder reaction for 1,3-butadiene includes the observation that cycloaddition should occur only from the s-cis conformer to produce czs-cyclohexene. This conformational selectivity, however, further implies that cycloaddition of s-trans- 1,3-butadiene should lead to trans-cyclohexene, but the s-trans region of this potential surface has remained unexplored. A study of this problem shows that the concerted and stepwise reaction paths exist for both diene conformers, connecting them to the respective cyclohexene isomers.661 It is also demonstrated that the usual paradigm for the Diels-Alder reactions is incomplete a thorough understanding of this archetypal reaction requires consideration of the full range of processes shown in Scheme 6.10, not just those involving the s-cis conformer. 

A long chain of amino acids attached end-to-end has many possible ways to fold. The final shape, or conformation, of a folded protein molecule is determined by its unique sequence of amino acids and by the effects of environmental conditions on amino acid side chains. The conformation selected is the one that is most stable because it has the lowest free energy (Bloomfield 1979). This conformation is designated the native state of the protein. 

Newman-Tancredi A, Cussac D, Marini L, Millan MJ. Antibody capture assay reveals bell-shaped concentration-response isotherms for h5-HTlA receptor-mediated G alpha(i3) activation conformational selection by high-efficacy agonists, and relationship to trafficking of receptor signaling. Mol Pharmacol 2002 62 590-601. 

Conformational Selection Using a 3,5-O-Di-tert-Butylsilylidene Protecting Group... 

Bradley, A. Z. Kociolek, M. G. Johnson, R. P. Conformational selectivity in the Diels-Alder cycloaddition predictions for reactions of s-trans-1,3-butadiene, 7. Org. Chem. 2000, 65, 7134-7138. 

Further, for antibody catalysis the methyl ester is too small to be an effective epitope but the participation could be induced if an antibody were able to recruit cocaine from the chair conformation to the less stable boat form (see Fig. 4 for the structure) and reorient the syn-protonated amine and benzoyl ester into proximity. Antibodies can provide significant binding energy and in principle antibody binding could effect conformer selection and promotion of substrate-assisted catalysis. To examine this idea, a detailed computational analysis [89] of the energetics of this reaction was also performed for design of novel TSA structures for the alkaline hydrolysis of boat cocaine in comparison with the hydrolysis of chair cocaine. 

Receptor Flexibility in Computational Design Induced-Fit Versus Conformational Selection Enthalpy-Entropy Compensation (EEC) Allostery Conclusion... 

The focus of this review article will be on the interaction between macromolecules and small-molecule ligands. The discussion will first center on the thermodynamic and kinetic characteristics that are used to measure the extent of binding. Subsequently, we discuss the interactions at the atomic level that drive complex formation. Then, a discussion follows of some tools available to predict macroscopic properties from microscopic properties. We then briefly discuss macromolec-ular motions as well as various aspects of receptor-ligand that have attracted renewed attention, such as conformational selection versus induced-fit, enthalpy-entropy compensation effect, and protein allostery. 

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