Garrido Nuno M, Queimada António J, Jorge Miguel, Macedo Eugénia A, Economou Ioannis G
Laboratory of Separation and Reaction Engineering (LSRE), Departamento de Engenharia Química, Faculdade de Engenharia, Universidade do Porto, Rua do Dr. Roberto Frias, 4200-465 Porto, Portugal and Molecular Thermodynamics and Modeling of Materials Laboratory, Institute of Physical Chemistry, National Center for Scientific Research "Demokritos", GR-153 10, Aghia Paraskevi Attikis, Greece.
J Chem Theory Comput. 2009 Sep 8;5(9):2436-46. doi: 10.1021/ct900214y.
The 1-octanol/water partition coefficient is an important thermodynamic variable usually employed to understand and quantify the partitioning of solutes between aqueous and organic phases. It finds widespread use in many empirical correlations to evaluate the environmental fate of pollutants as well as in the design of pharmaceuticals. The experimental evaluation of 1-octanol/water partition coefficients is an expensive and time-consuming procedure, and thus, theoretical estimation methods are needed, particularly when a physical sample of the solute may not yet be available, such as in pharmaceutical screening. 1-Octanol/water partition coefficients can be obtained from Gibbs free energies of solvation of the solute in both the aqueous and the octanol phases. The accurate evaluation of free energy differences remains today a challenging problem in computational chemistry. In order to study the absolute solvation Gibbs free energies in 1-octanol, a solvent that can mimic many properties of important biological systems, free energy calculations for n-alkanes in the range C1-C8 were performed using molecular simulation techniques, following the thermodynamic integration approach. In the first part of this paper, we test different force fields by evaluating their performance in reproducing pure 1-octanol properties. It is concluded that all-atom force fields can provide good accuracy but at the cost of a higher computational time compared to that of the united-atom force fields. Recent versions of united-atom force fields, such as Gromos and TraPPE, provide satisfactory results and are, thus, useful alternatives to the more expensive all-atom models. In the second part of the paper, the Gibbs free energy of solvation in 1-octanol is calculated for several n-alkanes using three force fields to describe the solutes, namely Gromos, TraPPE, and OPLS-AA. Generally, the results obtained are in excellent agreement with the available experimental data and are of similar accuracy to commonly used QSPR models. Moreover, we have estimated the Gibbs free energy of hydration for the different compounds with the three force fields, reaching average deviations from experimental data of less than 0.2 kcal/mol for the case of the Gromos force field. Finally, we systematically compare different strategies to obtain the 1-octanol/water partition coefficient from the simulations. It is shown that a fully predictive method combining the Gromos force field in the aqueous phase and the OPLS-AA/TraPPE force field for the organic phase can give excellent predictions for n-alkanes up to C8 with an absolute average deviation of 0.1 log P units to the experimental data.
正辛醇/水分配系数是一个重要的热力学变量，通常用于理解和量化溶质在水相和有机相之间的分配。它在许多用于评估污染物环境归宿的经验关联式以及药物设计中都有广泛应用。正辛醇/水分配系数的实验评估是一个昂贵且耗时的过程，因此需要理论估算方法，特别是当溶质的物理样品可能尚未可得时，例如在药物筛选中。正辛醇/水分配系数可从溶质在水相和正辛醇相中的溶剂化吉布斯自由能获得。准确评估自由能差在当今计算化学中仍然是一个具有挑战性的问题。为了研究在能模拟许多重要生物系统性质的溶剂正辛醇中的绝对溶剂化吉布斯自由能，采用热力学积分方法，使用分子模拟技术对C1 - C8范围内的正构烷烃进行了自由能计算。在本文的第一部分，我们通过评估不同力场在重现纯正辛醇性质方面的性能来进行测试。得出的结论是，与联合原子力场相比，全原子力场可以提供良好的精度，但代价是计算时间更长。联合原子力场的最新版本，如Gromos和TraPPE，提供了令人满意的结果，因此是更昂贵的全原子模型的有用替代方案。在本文的第二部分，使用三种描述溶质的力场，即Gromos、TraPPE和OPLS - AA，计算了几种正构烷烃在正辛醇中的溶剂化吉布斯自由能。一般来说，所获得的结果与现有的实验数据非常吻合，并且与常用的定量构效关系模型具有相似的精度。此外，我们用这三种力场估算了不同化合物的水合吉布斯自由能，对于Gromos力场的情况，与实验数据的平均偏差小于0.2千卡/摩尔。最后，我们系统地比较了从模拟中获得正辛醇/水分配系数的不同策略。结果表明，一种将水相中的Gromos力场和有机相中的OPLS - AA/TraPPE力场相结合的完全预测方法，对于C8以下的正构烷烃可以给出出色的预测，与实验数据的绝对平均偏差为0.1 log P单位。
