At both extremes of the conceptual design space we see difficult obstacles. On one hand there are natural proteins which are easily synthesized but are very difficult to design, on the other hand there are lattices of MBBs which are easy to design but problematic to synthesize and assemble. What has not yet been sufficiently explored is the territory in between these extremes. A trade-off can be made along the lines of the reverse protein folding problem. Synthesizing a largely linear or slightly cross-linked polymer is not too difficult. But one would like to increase the designability by using unorthodox amino-acid-like moieties which, through the bulkiness and rigidity of their artificial side chains, are able to restrict the conformational freedom of the folding polymer considerably. This can substantially reduce the combinatorial explosion of different conformations and thus the search space that has to be considered to find satisfying solutions. In this domain, design is not as intractable as in natural proteins, but is nevertheless more difficult than humans would want to be confronted with directly. To assist the human designer, computer-aided design tools are necessary that are able to autonomously generate proposals for polymers that fold into a tightly packed structure.
The author is currently working on such a program, called CavityStuffer. It generates its proposals by "growing" polymers blindly within a given volume, the surface of which has been prescribed to atomic precision. In a randomized fashion, it chooses sites on the tree-like polymer for further attachment and elongation. Once a site has been chosen, a moiety (monomer) is selected from a library of allowed moieties, similar in concept to allowed moves in a game of chess. The moieties are stored in the library as rigid, three-dimensional puzzle-pieces (as rotamers); so the CavityStuffer program works by trying to fit three-dimensional geometric shapes into the given volume. Whenever a chosen moiety does not fit (i.e. if it clashes with other atoms already in place), it is discarded, and a different moiety will be tried instead. This scheme largely avoids the expensive numerical tasks encountered in energy calculations (which are commonly used for studies of protein folding), because clash-detection is quick. Because the generation of individual proposals is fast, a large number can be generated automatically without human super-vision and sorted according to how well they fill the volume. There are various places in the program where one could add in smarter and higher-level strategies than the random selection mechanism used now.
Currently the basic machinery of the CavityStuffer program has been implemented and is working. One can let it build tree-like molecules using moieties provided by a library. There are also tools to help construct the moiety-library, and there are facilities for input and output via PDB files. But with a simplistic demo-version of the moiety-library, the packing of the polymer is not yet very good. More work has to go into a careful design of good moiety-libraries which contain a high enough diversity of rotamers. Better packing strategies need to be added as well. Interested readers who would like to stay informed on this project are welcome to send e-mail to firstname.lastname@example.org.