Predicting hydration free energies using all-atom molecular dynamics simulations and multiple starting conformations

被引:89
|
作者
Klimovich, Pavel V. [1 ]
Mobley, David L. [1 ]
机构
[1] Univ New Orleans, Dept Chem, New Orleans, LA 70148 USA
关键词
Hydration; Alchemical; Free energy; Molecular dynamics; SOLVATION FREE-ENERGIES; BINDING FREE-ENERGIES; EFFICIENT GENERATION; ABSORPTION-SPECTRA; AM1-BCC MODEL; CYANURIC ACID; FORCE-FIELDS; CHALLENGE; SOLVENT; ANALOGS;
D O I
10.1007/s10822-010-9343-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Molecular dynamics simulations in explicit solvent were applied to predict the hydration free energies for 23 small organic molecules in blind SAMPL2 test. We found good agreement with experimental results, with an RMS error of 2.82 kcal/mol over the whole set and 1.86 kcal/mol over all the molecules except several hydroxyl-rich compounds where we find evidence for a systematic error in the force field. We tested two different solvent models, TIP3P and TIP4P-Ew, and obtained very similar hydration free energies for these two models; the RMS difference was 0.64 kcal/mol. We found that preferred conformation of the carboxylic acids in water differs from that in vacuum. Surprisingly, this conformational change is not adequately sampled on simulation timescales, so we apply an umbrella sampling technique to include free energies associated with the conformational change. Overall, the results of this test reveal that the force field parameters for some groups of molecules (such as hydroxyl-rich compounds) still need to be improved, but for most compounds, accuracy was consistent with that seen in our previous tests.
引用
收藏
页码:307 / 316
页数:10
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