Evaluating nonpolarizable nucleic acid force fields: A systematic comparison of the nucleobases hydration free energies and chloroform‐to‐water partition coefficients

Nucleic acid force fields have been shown to reproduce structural properties of DNA and RNA very well, but comparative studies with respect to thermodynamic properties are rare. As a test for thermodynamic properties, we have computed hydration free energies and chloroform‐to‐water partition coefficients of nucleobases using the AMBER‐99, AMBER‐gaff, CHARMM‐27, GROMOS‐45a4/53a6 and OPLS‐AA force fields. A mutual force field comparison showed a very large spread in the calculated thermodynamic properties, demonstrating that some of the parameter sets require further optimization. The choice of solvent model used in the simulation does not have a significant effect on the results. Comparing the hydration free energies obtained by the various force fields to the adenine and thymine experimental values showed a very large deviation for the GROMOS and AMBER parameter sets. Validation against experimental partition coefficients showed good agreement for the CHARMM‐27 parameter set. In view of mutation studies, differences in partition coefficient between two bases were also compared, and good agreement between experiments and calculations was found for the AMBER‐99 parameter set. Overall, the CHARMM‐27 parameter set performs best with respect to the thermodynamic properties tested here. © 2012 Wiley Periodicals, Inc.