Unfavorable protein-ligand interactions

As discussed in the introduction, scoring functions still pose problems (see also Chapter 14). Some of these problems arise from insufficient consideration of details of favorable and unfavorable protein-ligand interactions. 

Structural data on unfavorable protein-ligand interactions are sparse. 

Work from Sturtevant s laboratory detailed the kinetics and thermodynamics of zinc binding to apocarbonic anhydrase (carbonate dehydratase) selected data are recorded in Table II (Henkens and Sturtevant, 1968 Henkens etal., 1969). The thermodynamic entropy term A5 at pH 7.0 is 88 e.u. (1 e.u. = 1 cal/mol-K), and this is essentially matched by the binding of zinc to the hexadentate ligand cyclohexylenediamine tetraacetate where AS = 82 e.u. At pH 7.0 the enthalpy of zinc-protein association is 9.8 kcal/mol, but this unfavorable term is overwhelmed by the favorable entropic contribution to the free energy (AG = AH - T AS), where —TAS = -26.2 kcal/mol at 298 K (25°C). Hence, the kinetics and thermodynamics of protein-zinc interaction in this example are dominated by very favorable entropy effects. 

Hydrophobic interactions are usually calibrated to the number of protein-ligand contacts or the size of the contact surface buried upon complex formation. By assigning a hydrophobicity character to the atoms or surface patches, more specific contact counts or surface measures can be obtained, such as hydrophobic-hydrophobic contacts as favorable and hydrophobic-hydrophilic contacts as unfavorable contributions to binding affinity. 

With the seven-helix bundle construct in hand, we turned our attention to incorporation of the three extracellular (EC) loops. The cytoplasmic loops were disregarded because they would not be involved in molecular recognition between the receptor and the SFLLRN ligand. Extracellular loop 3, the smallest of the three EC loops, was added first via the loop-search routine in the Biopolymer mode of Sybyl. The loop backbone choices found in the Brookhaven PDB were examined in 3-D and selected on the basis of their fit to the overall protein structure. After the side chains were added to EC3, some of them had to be rotated to avoid unfavorable steric interactions with other parts of the protein. Then, the entire protein was energy minimized. Extracellular loop 1 was then added, followed by EC2, and each time the loop selection was made after analyzing the protein in 3-D. Side chains of amino... 

Lysine also may form complexes with anionic ligands and thereby increase Am values. In addition, lysine may have an unfavorable effect on protein structure. Because it has a considerable hydrophobic moment, it may interact with hydrophobic sites on the protein, leading to perturbation of structure. Compatible solutes lack a propensity for interacting with peptide backbone linkages or amino acid side-chains, as discussed later. 

Figure 2 Role of water molecules in hydrogen bonds (upper part) and lipophilic interactions (lower part). In the unbound state (left side), the polar groups of the ligand and the protein form hydrogen bonds to water molecules. These water molecules are replaced upon complex formation. The hydrogen-bond inventory (total number of hydrogen bonds) does not change. In contrast, the formation of lipophilic contact increases the total number of hydrogen bonds due to the release of water molecules from the unfavorable lipophilic environment.

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