Testing the semi-explicit assembly model of aqueous solvation in the SAMPL4 challenge Libo Li • Ken A. Dill • Christopher J. Fennell Received: 15 November 2013 / Accepted: 16 January 2014 / Published online: 29 January 2014 Ó Springer International Publishing Switzerland 2014 Abstract Here, we test a method, called semi-explicit assembly (SEA), that computes the solvation free energies of molecules in water in the SAMPL4 blind test challenge. SEA was developed with the intention of being as accurate as explicit-solvent models, but much faster to compute. It is accurate because it uses pre-simulations of simple spheres in explicit solvent to obtain structural and thermodynamic quantities, and it is fast because it parses solute free energies into regionally additive quantities. SAMPL4 provided us the opportunity to make new tests of SEA. Our tests here lead us to the following conclusions: (1) The newest version, called Field-SEA, which gives improved predictions for highly charged ions, is shown here to per- form as well as the earlier versions (dipolar and quadru- polar SEA) on this broad blind SAMPL4 test set. (2) We find that both the past and present SEA models give sol- vation free energies that are as accurate as TIP3P. (3) Using a new approach for force field parameter optimiza- tion, we developed improved hydroxyl parameters that ensure consistency with neat-solvent dielectric constants, and found that they led to improved solvation free energies for hydroxyl-containing compounds in SAMPL4. We also learned that these hydroxyl parameters are not just fixing solvent exposed oxygens in a general sense, and therefore do not improve predictions for carbonyl or carboxylic-acid groups. Other such functional groups will need their own independent optimizations for potential improvements. Overall, these tests in SAMPL4 indicate that SEA is an accurate, general and fast new approach to computing solvation free energies. Keywords SAMPL  Semi-explicit assembly  Hydration  Free energy calculations  Implicit solvation Introduction In an effort to provide rapid and accurate estimates of hydration free energies for arbitrary solutes, we have recently developed a solvation method called semi-explicit assembly (SEA) [1, 2]. SEA is based on using an assembly approach, whereby we start with different small (atom- sized) spheres, and we simulate their solvation properties in some explicit-solvent model, such as TIP3P water [3]. We harvest these properties as a function of the van der Waals and electrostatic properties of the spheres, then at runtime for a given solute, we assemble appropriate collections of spheres and sum up the hydration free energy for the whole molecule (see Fig. 1). We have previously found that the SEA model using dipolar semi-explicit water accurately reproduces the results from explicit-solvent free energy calculations [2, 4]. In cases where explicit solvent calculations give good predictions of experimental Henry’s law constants, SEA gives similarly good estimates. In cases where explicit solvent calculations provide poor comparisons to experimental quantities, SEA usually does so too. This correspondence between SEA and explicit solvent Electronic supplementary material The online version of this article (doi:10.1007/s10822-014-9712-8) contains supplementary material, which is available to authorized users. L. Li  K. A. Dill Departments of Chemistry and Physics, Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, USA C. J. Fennell (&) Department of Chemistry, Oklahoma State University, Stillwater, OK 74078, USA e-mail: cfennell@gmail.com; christopher.fennell@okstate.edu 123 J Comput Aided Mol Des (2014) 28:259–264 DOI 10.1007/s10822-014-9712-8