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Empirical methods for computing molecular partition coefficients: II. Inclusion of conformational flexibility within fragment–based approaches
Author(s) -
Richards Nigel G. J.,
Williams Philip B.,
Tute Michael S.
Publication year - 1992
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560440210
Subject(s) - partition coefficient , solvation , chemistry , maxima and minima , octanol , molecular dynamics , conformational isomerism , molecule , computational chemistry , partition (number theory) , oniom , population , potential energy surface , implicit solvation , thermodynamics , physics , mathematics , organic chemistry , mathematical analysis , combinatorics , demography , sociology
A novel algorithm for computing the water/1‐octanol partition coefficient, log P , of conformationally flexible molecules, has been investigated using calculations upon a number of uncharged, linear dipeptides. In this method (which appears to be the first to consider explicitly the effects of the population of accessible conformational minima in both phases), the partition coefficient for each dipeptide was calculated from the overall energy change associated with moving the relevant gas‐phase conformational distribution into water and into 1‐octanol. These energies were computed using solvation contributions based upon the solvent accessible molecular surface area and two sets of empirical parameters. In these initial studies, gas‐phase conformational minima were generated using systematic search methods. While the standard error in the computed log P values was disappointing, reasonable agreement was observed between calculated and experimental log P values for the set of model dipeptides, especially when specific hydration interactions involving polar fragments were correctly included in the empirical solvation term. These results indicate that the physical basis of many correction factors employed in the ClogP algorithm for computing log P probably arise from neglect of the redistribution of conformer populations as flexible molecules partition between water and 1‐octanol.