I was using Tcl scripting in NAMD/VMD software for such a purpose: 1. creating a sparse box of molecules. 2. relaxing it and bringing it to some equilibrium state by either cooling or putting some external force.

I had good results with packmol (http://www.ime.unicamp.br/~martinez/packmol/) which starts fom a single PDB file and fills the desired (defined bu user) space with these moelcules using some algorithms, which optimize the packing. It's actually a pretty powerful program, which can also deal with mixtures and boxes/spheres of various geometries and sizes.

Packmol is really good.

Details about how to work with sparse box, on the example of Ascalaph program (http://www.biomolecular-modeling.com/Products.html).

1. Create 256 separated in space copies (menu – Build/Crystal).

Choose number of copies along the axes 8x8x4 = 256

Choose lattice parameter, sufficient to ensure that the molecules do not touch - 8 A.

Create copies (button Apply).

Create a periodic boundary conditions (menu – Settings/Boundary conditions – button Periodic box).

2. Orient each molecule randomly (Select all. Menu – Edit/Disorient selected molecules). Although for such small symmetric molecules as a benzene we do not need it.

3. Squeeze box using molecular dynamics.

To do this quickly, on the first phase use very strong barostat, say - pressure 10,000 atmospheres; Tau 0.02 ps. When the molecules come into contact (a few seconds, the density of 0.4 g/cm3) reduce the power of barostat. Otherwise, the model can break. Pressure 1000 atmospheres; Tau 0.2 ps. Turn on the Lowe thermostat. Otherwise temperature for a long time will not come to normal. When the density reaches normal (0.88 g/cm3 after 100 ps) stop dynamics and establish normal parameters.

Preliminary model is ready.

http://www.biomolecular-modeling.com/Products.html

I solved my problem, which was the same of the question, with the Packmol. I strongly recommend this package. In the code solvate.tcl there are a part to compute the size of the structure (maximum and minimum size on each direction) and then construct a box.