Ab initio models for receptor-ligand interactions in proteins. 4. Model assembly study of the catalytic mechanism of triosephosphate isomerase.

The catalytic mechanism of triosephosphate isomerase (TIM) was investigated with ab initio quantum mechanical calculations. Electrostatic interactions between the quantum mechanical active site and the protein and solvent environment were modeled using the finite difference Poission-Boltzman method. The complexes of TIM with the substrate dihydroxyacetone phosphate (DHAP), five possible intermediates and the product glyceraldehyde-3-phosphate (GAP) were optimized in the active-site model at the 3-21G(*) level and energy profile for the proton abstraction from DHAP by the active-site Glu 167 was calculated at the MP2/3-21G(*)13-21G(*) level. Calculated energetics of the enzyme reaction were found to be in reasonable agreement with the experimental findings. Calculations revealed that an enediol of the substrate is a probable intermediate in the enzyme reaction. It was suggested that the proton abstracted from the substrate by the active-site glutamate goes to the carbonyl oxygen of the substrate producing enediol intermediate either directly or after it is exchanged with solvent.

Model assembly study of the ligand binding by p-hydroxybenzoate hydroxylase: correlation between the calculated binding energies and the experimental dissociation constants.

The energies of binding of seven ligands by p-hydroxybenzoate hydroxylase (PHBH) were calculated theoretically. Direct enzyme-ligand interaction energies were calculated using the ab initio quantum mechanical model assembly of the active site at the 3-21G level. Solvation energies of the ligands needed in the evaluation of the binding energies were calculated with the semiempirical AM1-SM2 method and the long-range electrostatic interaction energies between the ligands and the protein matrix classically using the static charge distributions of the ligands and the protein. Energies for proton-transfer between the ligands' OH or SH substituent at position 4 and the active-site tyrosine within the ab initio model assemblies were calculated and compared to the corresponding pKas in aqueous solution. Excluding 3,4-dihydroxybenzoate, the natural product of PHBH, a linear relationship between the calculated binding energies and the experimental binding free energies was found with a correlation coefficient of 0.90. Contributions of the direct enzyme-ligand interaction energies, solvation energies and the long-range electrostatic interaction energies to the calculated binding energies were analyzed. The proton-transfer energies of the ligands with substituents ortho to the ionized OH were found to be perturbed less in the model calculations than the energies of their meta isomers as deduced from the corresponding pKas.

Quantum mechanical model assembly study on the energetics of binding of arabinose, fucose, and galactose to L-arabinose-binding protein.

Binding energies of L-arabinose, D-fucose, and D-galactose to L-arabinose-binding protein was investigated theoretically. The calculated binding energies were composed of three contributions: 1) direct ligand-active site interaction energies calculated using static ab initio model assemblies; 2) solvation energies of the ligands; and 3) long-range electrostatic interaction energies between the ligands and the protein matrix. The calculated binding energies and the contributions of the energy components were used to analyze the experimental affinities of the ligands.

Modelling of alpha 2-adrenergic ligands.

Six different ligands, which bind to alpha 2-adrenergic receptor were studied using molecular mechanics and quantum chemical methods. Superimposition was performed using low energy conformations resulting the common binding model. Both electrostatic and structural features of different compounds were compared. It is suggested, that the reason for agonism/antagonism is based on small structural differences in ligands. In agonists the distance between the cationic nitrogen and an aromatic ring plane was about 1 A shorter than in antagonists, whereas the distance between the same nitrogen and outmost part of ring atoms was about 1 A longer in agonists than in antagonists.

Quantum chemical study on the interaction of some bisphosphonates and Ca2+: the role of molecular electrostatic potentials in the prediction of binding geometry.

Molecular electrostatic potentials have been used to model the calcium binding properties of some bisphosphonate drugs, which are used to treat various bone diseases. The mechanism of action involves the binding of bisphosphonates to the bone surface, where calcium plays an important role. Electrostatic potential maps derived from ab initio partial charges have been compared with both the crystal structure and the fully optimized ab initio structure of (dichloro)methylene-bisphosphonate-calcium ion complex. Molecular electrostatic potentials can correctly predict the calcium binding geometry of bisphosphonate-type compounds and this type of information can be used in the practical drug design work.

Comparative molecular field analysis of some clodronic acid esters.

Comparative molecular field analysis (CoMFA) has been used as a three-dimensional quantitative structure-activity relationship (QSAR) method to correlate three different types of biological activity data with physicochemical properties of some clodronate ester analogues, which act as bone-resorption regulators in cell cultures and rats. The QSAR studies show the importance of the steric properties of these new bisphosphonate derivatives for the inhibition of bone resorption in bone cell cultures and for their bioavailability in rats. This information will be used in predicting the structure of new more potent bisphosphonic compounds.