Exploring Strong Interactions in Proteins with Quantum Chemistry and Examples of Their Applications in Drug Design

Abstract

ObjectivesThree strong interactions between amino acid side chains (salt bridge, cation-π, and amide bridge) are studied that are stronger than (or comparable to) the common hydrogen bond interactions, and play important roles in protein-protein interactions.MethodsQuantum chemical methods MP2 and CCSD(T) are used in calculations of interaction energies and structural optimizations.ResultsThe energies of three types of amino acid side chain interactions in gaseous phase and in aqueous solutions are calculated using high level quantum chemical methods and basis sets. Typical examples of amino acid salt bridge, cation-π, and amide bridge interactions are analyzed, including the inhibitor design targeting neuraminidase (NA) enzyme of influenza A virus, and the ligand binding interactions in the HCV p7 ion channel. The inhibition mechanism of the M2 proton channel in the influenza A virus is analyzed based on strong amino acid interactions.Conclusion(1) The salt bridge interactions between acidic amino acids (Glu- and Asp-) and alkaline amino acids (Arg+, Lys+ and His+) are the strongest residue-residue interactions. However, this type of interaction may be weakened by solvation effects and broken by lower pH conditions. (2) The cation- interactions between protonated amino acids (Arg+, Lys+ and His+) and aromatic amino acids (Phe, Tyr, Trp and His) are 2.5 to 5-fold stronger than common hydrogen bond interactions and are less affected by the solvation environment. (3) The amide bridge interactions between the two amide-containing amino acids (Asn and Gln) are three times stronger than hydrogen bond interactions, which are less influenced by the pH of the solution. (4) Ten of the twenty natural amino acids are involved in salt bridge, or cation-, or amide bridge interactions that often play important roles in protein-protein, protein-peptide, protein-ligand, and protein-DNA interactions.

Active Hydrogen Bond Network (AHBN) and Applications for Improvement of Thermal Stability and pH-Sensitivity of Pullulanase from Bacillus naganoensis

“…The hydroxyl group of Thr477 and the imidazole ring of His445 form a stable polar hydrogen-π bond, even stronger than the common hydrogen bonds [28,34]. On the other hand the His445 forms a hydrogen bond with water molecule W604, shown in Fig 6(A), by which Thr477 and His445 join in the AHBN of pullulanase BNPulA324.…”

“…After the mutation Thr477Asn, in the hydrogen-π bond the polar hydrogen group is changed from the hydroxyl group (-OH) of Thr477 to the amino group (-NH 2 ) of Asn477, and the distance decreases from 3.11 Å to 2.65 Å. The pK a value of His445 is affected by the polar hydrogen-π bond [28,34]. The stronger polar hydrogen-π bond between His445 and Asn477 is favorable to the hydrolytic catalysis reaction of pullulanase BNPulA324.…”

RFDTI: Using Rotation Forest with Feature Weighted for Drug-Target Interaction Prediction from Drug Molecular Structure and Protein Sequence

“…where TP is the number of drug-target pairs that are related to each other to be correctly identified; FP is the number of drug-target pairs that are related to each other to be incorrectly identified; TN is the number of drug-target pairs that are not related to each other to be correctly identified; FN is the number of drug-target pairs that are not related to each other to be incorrectly identified. Moreover, the receiver operating characteristic (ROC) curve [18][19][20] and area under the ROC curve (AUC) are used to visually display the performance of the classifier.…”

Four faces of the interaction between ions and aromatic rings

“…Further NCIs, like interactions between ions and electron-rich p systems, including aromatic rings, have also been studied, often with a view on supramolecular biochemistry. [1][2][3][4][5][6][7][8][9][10][11][12] The tunable physico-chemical properties of these ion2aromatic-ring (IAR) interactions have been exploited in the fields of drug design, [13] protein engineering, [14,15] and host-guest chemistry. [12] The IAR interactions offer improved selectivity, in some cases involving cooperative effects, [16] which can facilitate the design of artificial ion transporters [9] and sensors.…”

“…(23-37) > AP ? (14-21) > CP k (9-22) > AP k (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). A natural bond orbital analysis performed leads to a deeper qualitative understanding of the four interaction types.…”