Binding Affinities of Host–Guest, Protein–Ligand, and Protein–Transition‐State Complexes

Abstract

The affinities of hosts—ranging from small synthetic cavitands to large proteins—for organic molecules are well documented. The average association constants for the binding of organic molecules by cyclodextrins, synthetic hosts, and albumins in water, as well as of catalytic antibodies or enzymes for substrates are 103.5±2.5 M−1. Binding affinities are elevated to 108±2 M−1 for the complexation of transition states and biological antigens by antibodies or inhibitors by enzymes, and to 1016±4 M−1 for transition states with enzymes. The origins of the distributions of association constants observed for the broad range of host–guest systems are explored in this Review, and typical approaches to compute and analyze host–guest binding in solution are discussed. In many classes of complexes a rough correlation is found between the binding affinity and the surface area that is buried upon complexation. Enzymes transcend this effect and achieve transition‐state binding much greater than is expected from the surface areas.

Charge-Mediated Recognition of N-Terminal Tryptophan in Aqueous Solution by a Synthetic Host

“…It should be noted that the high stability of the Q8•MV•WGG complex (-7 kcal/mol) is rare for a synthetic host in aqueous solution, 21 and further supports the study of Q8 as a model for biomolecular receptors. As observed for the monomeric tryptophan derivatives, the peptide with a positive charge near the indole (WGG) binds Q8•MV with higher affinity than the peptide with a negative charge near the indole (GGW).…”

The Origins of Femtomolar Protein−Ligand Binding: Hydrogen-Bond Cooperativity and Desolvation Energetics in the Biotin−(Strept)Avidin Binding Site

“…Optimized structures of the isolated hydrogen-bonding residues for streptavidin and avidin model binding sites at the B3LYP/6-31+G(d,p) level. Comparison of bond lengths (Å) and charges (NPA) of isolated bicylic urea unit of biotin (8), the urea group when bound in the (strept)avidin model binding sites (9), and the conjugate base (10). Structures were optimized by B3LYP/6-31+G(d,p).…”

“…9 The biotin-(strept)avidin complexes generally exceed estimates of affinities from empirically determined free energy scoring functions and binding surveys. [10][11][12][13] The mechanism by which biotin-(strept)avidin exceeds normal highest protein-ligand affinities by 10 2 -10 4 M −1,9 has been subject of much interest.…”

Nanomolar Binding of Peptides Containing Noncanonical Amino Acids by a Synthetic Receptor

“…6 Despite the excellent selectivity observed in these systems, the lowest Kd values (for N-terminal phenylalanine) are in the 0.1-1 M range. Such affinities by artificial receptors in aqueous solution are considered relatively high by current standards in the field, 7 but a 100-fold or better boost in affinity would significantly increase the viability of in vivo applications.…”

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ABSTRACT: This paper describes the molecular recognition of phenylalanine derivatives and their peptides by the synthetic receptor cucurbit [7]uril (Q7). The 4-t-butyl and 4-aminomethyl derivatives of phenylalanine (tBuPhe and AMPhe) were identified from a screen to have 20-30-fold higher affinity than phenylalanine for Q7.

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