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Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain.

ABSTRACT: Thermodynamic parameters were determined for complex formation between the Grb2 SH2 domain and tripeptides of the general form Ac-pTyr-Xaa-Asn in which the Xaa residue bears a linear alkyl chain varying in length from 1-5 carbon atoms. Binding affinity increases upon adding a methylene group to the Ala derivative, but further chain extension gives no extra enhancement in potency. The thermodynamic signatures of the ethyl and n-propyl derivatives are virtually identical as are those for the n-butyl and n-pentyl analogs. Crystallographic analysis of the complexes reveals a high degree of similarity in the structure of the domain and the bound ligands with the notable exception that there is a gauche interaction in the side chains in the bound conformations of ligands having n-propyl, n-butyl, and n-pentyl groups. However, eliminating this unfavorable interaction by introducing a Z-double bond into the side chain of the n-propyl analog does not result in an increase in affinity. Increases in the amount of nonpolar surface that is buried upon ligand binding correlate with favorable changes in ΔH°, but these are usually offset by corresponding unfavorable changes in -TΔS°; there is little correlation of ΔCp with changes in the amount of buried nonpolar surface.

SUBMITTER: Myslinski JM

PROVIDER: S-EPMC3859442 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain.

Myslinski James M JM Clements John H JH Delorbe John E JE Martin Stephen F SF

ACS medicinal chemistry letters 20131101 11

Thermodynamic parameters were determined for complex formation between the Grb2 SH2 domain and tripeptides of the general form Ac-pTyr-Xaa-Asn in which the Xaa residue bears a linear alkyl chain varying in length from 1-5 carbon atoms. Binding affinity increases upon adding a methylene group to the Ala derivative, but further chain extension gives no extra enhancement in potency. The thermodynamic signatures of the ethyl and <i>n</i>-propyl derivatives are virtually identical as are those for th ...[more]

PMID: 24349642

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Project description:Understanding how making structural changes in small molecules affects their binding affinities for targeted proteins is central to improving strategies for rational drug design. To assess the effects of varying the nature of nonpolar groups upon binding entropies and enthalpies, we designed and prepared a set of Grb2-SH2 domain ligands, Ac-pTyr-Ac6c-Asn-(CH2)n-R, in which the size and electrostatic nature of R groups at the pTyr+3 site were varied. The complexes of these ligands with the Grb2-SH2 domain were evaluated in a series of studies in which the binding thermodynamics were determined using isothermal titration calorimetry, and binding interactions were examined in crystallographic studies of two different complexes. Notably, adding nonpolar groups to the pTyr+3 site leads to higher binding affinities, but the magnitude and energetic origins of these effects vary with the nature of the R substituent. For example, enhancements to binding affinities using aliphatic R groups are driven by more favorable changes in binding entropies, whereas aryl R groups improve binding free energies through a combination of more favorable changes in binding enthalpies and entropies. However, enthalpy/entropy compensation plays a significant role in these associations and mitigates against any significant variation in binding free energies, which vary by only 0.8 kcal•mol-1, with changes in the electrostatic nature and size of the R group. Crystallographic studies show that differences in ΔG° or ΔH° correlate with buried nonpolar surface area, but they do not correlate with the total number of polar or van der Waals contacts. The relative number of ordered water molecules and relative order in the side chains at pTyr+3 correlate with differences in -TΔS°. Overall, these studies show that burial of nonpolar surface can lead to enhanced binding affinities arising from dominating entropy- or enthalpy-driven hydrophobic effects, depending upon the electrostatic nature of the apolar R group.

Project description:Santa Barbara Amorphous-15 (SBA) is a stable and mesoporous silica material. Quaternized SBA-15 with alkyl chains (QSBA) exhibits electrostatic attraction for anionic molecules via the N+ moiety of the ammonium group, whereas its alkyl chain length determines its hydrophobic interactions. In this study, QSBA with different alkyl chain lengths were synthesized using the trimethyl, dimethyloctyl, and dimethyoctadecyl groups (C1QSBA, C8QSBA, and C18QSBA, respectively). Carbamazepine (CBZ) is a widely prescribed pharmaceutical compound, but is difficult to remove using conventional water treatments. The CBZ adsorption characteristics of QSBA were examined to determine its adsorption mechanism by changing the alkyl chain length and solution conditions (pH and ionic strength). A longer alkyl chain resulted in slower adsorption (up to 120 min), while the amount of CBZ adsorbed was higher for longer alkyl chains per unit mass of QSBA at equilibrium. The maximum adsorption capacities of C1QSBA, C8QSBA, and C18QSBA, were 3.14, 6.56, and 24.5 mg/g, respectively, as obtained using the Langmuir model. For the tested initial CBZ concentrations (2-100 mg/L), the adsorption capacity increased with increasing alkyl chain length. Because CBZ does not dissociate readily (pKa = 13.9), stable hydrophobic adsorption was observed despite the changes in pH (0.41-0.92, 1.70-2.24, and 7.56-9.10 mg/g for C1QSBA, C8QSBA, and C18QSBA, respectively); the exception was pH 2. Increasing the ionic strength from 0.1 to 100 mM enhanced the adsorption capacity of C18QSBA from 9.27 ± 0.42 to 14.94 ± 0.17 mg/g because the hydrophobic interactions were increased while the electrostatic attraction of the N+ was reduced. Thus, the ionic strength was a stronger control factor determining hydrophobic adsorption of CBZ than the solution pH. Based on the changes in hydrophobicity, which depends on the alkyl chain length, it was possible to enhance CBZ adsorption and investigate the adsorption mechanism in detail. Thus, this study aids the development of adsorbents suitable for pharmaceuticals with controlling molecular structure of QSBA and solution conditions.

Dataset Information

Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain.

Publications

Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain.

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