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Расчет подвижности и энтропии связывания молекул в кристаллах

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Abstract

A simple method for evaluating a range of molecular movements in crystals has been developed. This estimate is needed to calculate the entropy of binding, in particular in protein-ligand complexes. The estimate is based on experimental data concerning the enthalpy of sublimation and saturated vapor pressure obtained for 15 organic crystals with melting temperatures of 25-80°С. For this set, we calculated the values of the average range and the corresponding average amplitude of molecular movements in crystals that constituted 0.75 ± 0.14 Å and 0.18 ± 0.03 Å, respectively. The entropy of sublimation calculated based on the average range of molecular movements in crystals was well consistent with the experimental data.

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Computational prediction of protein-ligand binding modes provides useful information on the relationship between structure and activity needed for drug design. A statistical rescoring method that incorporates entropic effect is proposed to improve the accuracy of binding mode prediction. A probability function for two sampled conformations to belong to the same broad basin in the potential energy surface is introduced to estimate the contribution of the state represented by a sampled conformation to the configurational integral. The rescoring function is reduced to the colony energy introduced by Xiang et al. (Proc Natl Acad Sci USA 2002;99:7432-7437) when a particular functional form for the probability function is used. The scheme is applied to rescore protein-ligand complex conformations generated by AutoDock. It is demonstrated that this simple rescoring improves prediction accuracy substantially when tested on 163 protein-ligand complexes with known experimental structures. For example, the percentage of complexes for which predicted ligand conformations are within 1 A root-mean-square deviation from the native conformations is doubled from about 20% to more than 40%. Rescoring with 11 different scoring functions including AutoDock scoring functions were also tested using the ensemble of conformations generated by Wang et al. (J Med Chem 2003;46:2287-2303). Comparison with other methods that use clustering and estimation of conformational entropy is provided. Examination of the docked poses reveals that the rescoring corrects the predictions in which ligands are tightly fit into the binding pockets and have low energies, but have too little room for conformational freedom and thus have low entropy.
База данных А2 по термодинамическим характеристикам молекулярных кристаллов. Приложение к статье [27] тех же авторов в Молекуляр. биология
  • Л Б Переяславец
  • А В Финкельштейн
Переяславец Л.Б., Финкельштейн А.В. 2011. База данных А2 по термодинамическим характеристикам молекулярных кристаллов. Приложение к статье [27] тех же авторов в Молекуляр. биология. 44, 340-354 (2010). http://phys.protres.ru/resources/FFS/A2.pdf
Силовое поле FFSol для расчета взаимодействий молекул в водном окружении
  • Л Б Переяславец
  • А В Финкельштейн
Переяславец Л.Б., Финкельштейн А.В. 2010. Силовое поле FFSol для расчета взаимодействий молекул в водном окружении. Молекуляр. биология. 44, 340-354.
Дополненная база данных А2 [29] по характеристикам молекулярных кристаллов
  • А В Финкельштейн
Финкельштейн А.В. 2014. Дополненная база данных А2 [29] по характеристикам молекулярных кристаллов. http://phys.protres.ru/resources/FFS/ Addition%20to%20A2.pdf