Swarup, generally combinatorial optimization problems are hard to be optimized. I do not know your problem in depth, anyway let me suggest to use Genetic Algorithms. Accordingly to my experience in combinatorial optimization, they are the most suitable to solve that kind of problems. Computer language? The easiest way is VBA within MS Excel, otherwise Matlab package! 

Cannot be done, we do not understand yet, what are the exact rules of protein folding, we only know some of basic principles and sometimes it is enough to fold some small proteins if we are lucky and have a lot of computational power

if I understood correctly what you have done:

You had sequences (e.g. from PDB) and then changed randomly up to 35% of residues, and now you would like to know which one will fold into similar to "seed" structure?

Then I would say: almost none. Even small changes (if not done with caution) e.g. 3% can destroy fold (and function) of the protein (most of genetic disorders are point mutations) . We even know examples that this 3% can completely reverse fold (from alpha helical to beta-sheet protein)

Of course, you can use homology based approach to filter your sequences, to find those which should in principle resemble your "seed", but it is far from saying that they fold in the same structure, they will be similar (e.g. 3-4 A). This approach is useful if you want to analyse individual protein, but if you want to derive from it some general rules then it will not help much. Moreover, people already introduced alignment information in most of protein folding analysis, so to be better you need to add something new.

even the problem of protein structure comparison is hard (comparing the folded protein against the target) .

Maybe for the current state of protein structure prediction (which is you may be wanting for), check CASP or CAFASP.

"The goal of CAFASP is to evaluate the performance of fully automatic structure prediction servers available to the community"

Good luck

David

Thank for the valuable suggestions