Evaluation of the molecular configuration integral in all degrees of freedom for the direct calculation of binding free energies: Application to the enantioselective binding of amino acid derivatives to synthetic host molecules
Evaluation of the molecular configuration integral in all degrees of freedom for the direct calculation of binding free energies: Application to the enantioselective binding of amino acid derivatives to synthetic host molecules
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DOI：
10.1021/ja971573n
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发表时间：
1997-10-22
影响因子：
15
通讯作者：
Kolossvary, I
中科院分区：
文献类型：
--
作者：
Kolossvary, I
A novel theoretical approach has been introduced recently for the direct calculation of conformational free energies without the need for expensive free energy simulations. 1 The new algorithm termed mode integration (MINTA) is based on a particularly efficient implementation of importance sampling Monte Carlo integration. MINTA allows, for the first time, the molecular configuration integral of molecular complexes of real chemical interest to be solved in all degrees of freedom, utilizing a continuum solvation model. The MINTA method was applied here to predict the enantioselective binding of R-amino acid derivatives to podand ionophore hosts, and peptide ligands to C3-symmetric synthetic receptors. In one particular case, the correct MINTA prediction of a significant, 1.5 kcal/mol entropic stabilization of the L-Ala peptide ligand with respect to its D-Ala enantiomer in binding to the receptor was elucidated by electronic structure calculations. The statistical-thermodynamic foundation of the calculation of binding affinities of molecular complexes is quite complex, 2 but for most practical problems, the stability of host-guest complexes can be formulated in terms of binding free energy (BFE) differences. 3 For example, one wishes to calculate the BFE difference (ΔΔGL-D) ΔGL-ΔGD) between the L and D enantiomers of a ligand bound to an enantioselective host. The direct calculation of ΔΔGL-D, in the classical sense, involves the evaluation of the molecular configuration integral
