Dataset Information

Protein-Ligand CH-π Interactions: Structural Informatics, Energy Function Development, and Docking Implementation.

ABSTRACT: Here, we develop an empirical energy function based on quantum mechanical data for the interaction between methane and benzene that captures the contribution from CH-π interactions. Such interactions are frequently observed in protein-ligand crystal structures, particularly for carbohydrate ligands, but have been hard to quantify due to the absence of a model for CH-π interactions in typical molecular mechanical force fields or docking scoring functions. The CH-π term was added to the AutoDock Vina (AD VINA) scoring function enabling its performance to be evaluated against a cohort of more than 1600 occurrences in 496 experimental structures of protein-ligand complexes. By employing a conformational grid search algorithm, inclusion of the CH-π term was shown to improve the prediction of the preferred orientation of flexible ligands in protein-binding sites and to enhance the detection of carbohydrate-binding sites that display CH-π interactions. Last but not least, this term was also shown to improve docking performance for the CASF-2016 benchmark set and a carbohydrate set.

SUBMITTER: Xiao Y

PROVIDER: S-EPMC10448718 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Protein-Ligand CH-π Interactions: Structural Informatics, Energy Function Development, and Docking Implementation.

Xiao Yao Y Woods Robert J RJ

Journal of chemical theory and computation 20230726 16

Here, we develop an empirical energy function based on quantum mechanical data for the interaction between methane and benzene that captures the contribution from CH-π interactions. Such interactions are frequently observed in protein-ligand crystal structures, particularly for carbohydrate ligands, but have been hard to quantify due to the absence of a model for CH-π interactions in typical molecular mechanical force fields or docking scoring functions. The CH-π term was added to the AutoDock V ...[more]

PMID: 37493980

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Project description:Glycan-binding proteins, or lectins, recognize distinct structural elements of polysaccharides, to mediate myriad biological functions. Targeting glycan-binding proteins involved in human disease has been challenging due to an incomplete understanding of the molecular mechanisms that govern protein-glycan interactions. Bioinformatics and structural studies of glycan-binding proteins indicate that aromatic residues with the potential for CH-π interactions are prevalent in glycan-binding sites. However, the contributions of these CH-π interactions to glycan binding and their relevance in downstream function remain unclear. An emblematic lectin, human galectin-3, recognizes lactose and N-acetyllactosamine-containing glycans by positioning the electropositive face of a galactose residue over the tryptophan 181 (W181) indole forming a CH-π interaction. We generated a suite of galectin-3 W181 variants to assess the importance of these CH-π interactions to glycan binding and function. As determined experimentally and further validated with computational modeling, variants with smaller or less electron-rich aromatic side chains (W181Y, W181F, W181H) or sterically similar but nonaromatic residues (W181M, W181R) showed poor or undetectable binding to lactose and attenuated ability to bind mucins or agglutinate red blood cells. The latter functions depend on multivalent binding, highlighting that weakened CH-π interactions cannot be overcome by avidity. Two galectin-3 variants with disrupted hydrogen bonding interactions (H158A and E184A) showed similarly impaired lactose binding. Molecular simulations demonstrate that all variants have decreased binding orientation stability relative to native galectin-3. Thus, W181 collaborates with the endogenous hydrogen bonding network to enhance binding affinity for lactose, and abrogation of these CH-π interactions is as deleterious as eliminating key hydrogen bonding interactions. These findings underscore the critical roles of CH-π interactions in carbohydrate binding and lectin function and will aid the development of novel lectin inhibitors.

Project description:Proline residues have unique roles in protein folding, structure, and function. Proline and the aromatic amino acids comprise the encoded cyclic protein residues. Aromatic protein side chains are defined by their negatively charged π faces, while the faces of the proline ring are partially positively charged. This polarity results from their two-point connection of the side chain to the electron-withdrawing protein backbone, and the lower electronegativity of hydrogen compared to carbon, nitrogen, and oxygen. The hydrogens adjacent to the carbonyl and amide nitrogen, Hα and Hδ, respectively, are the most partially positive. Proline's side chain is also conformationally restricted, allowing for interaction with aromatic residues with minimal entropic or steric penalty. Proline and aromatic residues can interact favorably with each other, due to both the hydrophobic effect and the interaction between the π aromatic face and the polarized C-H bonds, called a CH/π interaction. Aromatic-proline interactions can occur locally, for example, to stabilize cis-amide bonds, and over larger distances, in the tertiary structures of proteins, and intermolecularly in protein-protein interactions. In peptides and proteins, aromatic-proline sequences more readily adopt cis-prolyl amide bonds, where the aromatic ring interacts with the proline ring in the cis conformation. In aromatic-proline sequences, Trp and Tyr are more likely to induce cis-amide bonds than Phe, suggesting an aromatic electronic effect. This result would be expected for a CH/π interaction, in which a more electron-rich aromatic would have a stronger (more cis-stabilizing) interaction with partial positive charges on prolyl hydrogens. In this Account, we describe our investigations into the nature of local aromatic-proline interactions, using peptide models. We synthesized a series of 26 peptides, TXPN, varying X from electron-rich to electron poor aromatic amino acids, and found that the population of cis-amide bond (Ktrans/cis) is tunable by aromatic electronics. With 4-substituted phenylalanines, we observed a Hammett correlation between aromatic electronics and Ktrans/cis, with cis-trans isomerism electronically controllable by 1.0 kcal/mol. All aromatic residues exhibit a higher cis population than Ala or cyclohexylalanine, with Trp showing the strongest aromatic-proline interaction. In addition, proline stereoelectronic effects can modulate cis-trans isomerism by an additional 1.0 kcal/mol. The aromatic-proline interaction is enthalpic, consistent with its description as a CH/π interaction. Proline-aromatic sequences can also promote cis-prolyl bonds, either through interactions of the aromatic ring with the preceding cis-proline or with the Hα prior to cis-proline. Within proline-rich peptides, sequences commonly found in natively disordered proteins, aromatic residues promote multiple cis-amide bonds due to multiple favorable aromatic-proline interactions. Collectively, we found aromatic-proline interactions to be significantly CH/π in nature, tunable by aromatic electronics. We discuss these data in the context of aromatic-proline and aromatic-glycine interactions in local structure, in tertiary structure, in protein-protein interactions, and in protein assemblies.

Dataset Information

Protein-Ligand CH-π Interactions: Structural Informatics, Energy Function Development, and Docking Implementation.

Publications

Protein-Ligand CH-π Interactions: Structural Informatics, Energy Function Development, and Docking Implementation.

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