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The flexibility-complementarity dichotomy in receptor-ligand interactions.

ABSTRACT: Synthetic supramolecular complexes provide an opportunity for quantitative systematic exploration of the relationship between chemical structure and molecular recognition phenomena. A family of closely related zinc porphyrin-pyridine complexes was used to examine the interplay of conformational flexibility and geometric complementarity in determining the selectivity of molecular recognition events. The association constants of 48 zinc porphyrin-pyridine complexes were measured in two different solvents, toluene and 1,1,2,2-tetrachloroethane (TCE). These association constants were used to construct 32 chemical double mutant cycles to dissect the free energy contributions of intramolecular H-bonds between the phenol side arms of the porphyrins and the ester or amide side arms of the pyridine ligands. Effective molarities (EM) for the intramolecular interactions were determined by comparison with the corresponding intermolecular H-bonding interactions. The values of EM do not depend on the solvent and are practically identical for amide and ester H-bond acceptors located at the same site on the ligand framework. However, there are variations of an order of magnitude in EM depending on the flexibility of the linker used to connect the H-bond acceptors to the pyridine ligands. Rigid aromatic linkers give values of EM that are an order of magnitude higher than the values of EM for the corresponding ester linkers, which have one additional torsional degree of freedom. However, the most flexible ether linkers give values of EM that are also higher than the values of EM for the corresponding ester linkers, which have one less torsional degree of freedom. Although the penalty for conformational restriction on binding is higher for the more flexible ether linkers, this flexibility allows optimization of the geometric complementarity of the ligand for the receptor, so there is a trade off between preorganization and fit.

SUBMITTER: Sun H

PROVIDER: S-EPMC5811160 | biostudies-other | 2015 Feb

REPOSITORIES: biostudies-other

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The flexibility-complementarity dichotomy in receptor-ligand interactions.

Sun Hongmei H Hunter Christopher A CA Llamas Eva Marina EM

Chemical science 20141215 2

Synthetic supramolecular complexes provide an opportunity for quantitative systematic exploration of the relationship between chemical structure and molecular recognition phenomena. A family of closely related zinc porphyrin-pyridine complexes was used to examine the interplay of conformational flexibility and geometric complementarity in determining the selectivity of molecular recognition events. The association constants of 48 zinc porphyrin-pyridine complexes were measured in two different s ...[more]

PMID: 29560233

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Project description:We have developed a novel structure-based chemoinformatics approach to search for Complimentary Ligands Based on Receptor Information (CoLiBRI). CoLiBRI is based on the representation of both receptor binding sites and their respective ligands in a space of universal chemical descriptors. The binding site atoms involved in the interaction with ligands are identified by the means of a computational geometry technique known as Delaunay tessellation as applied to X-ray characterized ligand-receptor complexes. TAE/RECON multiple chemical descriptors are calculated independently for each ligand as well as for its active site atoms. The representation of both ligands and active sites using chemical descriptors allows the application of well-known chemometric techniques in order to correlate chemical similarities between active sites and their respective ligands. We have established a protocol to map patterns of nearest neighbor active site vectors in a multidimensional TAE/RECON space onto those of their complementary ligands and vice versa. This protocol affords the prediction of a virtual complementary ligand vector in the ligand chemical space from the position of a known active site vector. This prediction is followed by chemical similarity calculations between this virtual ligand vector and those calculated for molecules in a chemical database to identify real compounds most similar to the virtual ligand. Consequently, the knowledge of the receptor active site structure affords straightforward and efficient identification of its complementary ligands in large databases of chemical compounds using rapid chemical similarity searches. Conversely, starting from the ligand chemical structure, one may identify possible complementary receptor cavities as well. We have applied the CoLiBRI approach to a data set of 800 X-ray characterized ligand-receptor complexes in the PDBbind database. Using a k nearest neighbor (kNN) pattern recognition approach and variable selection, we have shown that knowledge of the active site structure affords identification of its complimentary ligand among the top 1% of a large chemical database in over 90% of all test active sites when a binding site of the same protein family was present in the training set. In the case where test receptors are highly dissimilar and not present among the receptor families in the training set, the prediction accuracy is decreased; however, CoLiBRI was still able to quickly eliminate 75% of the chemical database as improbable ligands. CoLiBRI affords rapid prefiltering of a large chemical database to eliminate compounds that have little chance of binding to a receptor active site.

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The flexibility-complementarity dichotomy in receptor-ligand interactions.

Publications

The flexibility-complementarity dichotomy in receptor-ligand interactions.

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