A FREE-ENERGY ANALYSIS BY UNFOLDING APPLIED TO 125-MERS ON A CUBIC LATTICE

Background: A common approach to the protein folding problem involves computer simulation of folding using lattice models of amino acid sequ ences. Key factors for good performance in such models are the correct choice of the temperature and the average interaction energy between residues. In order to push the lattice approach to its limit it is imp ortant to have a method to adjust these parameters for optimal folding that is not limited by our ability to successfully simulate folding i n a reasonable time. Results: In this study, we adopt a simple cubic-l attice model and present a method for calculating the free energy of a chain as a function of the number of native contacts. This does not r equire that we are able to fold the sequence by simulation and it prov ides a method of estimating the folding transition temperature. For a given set of parameters, the free energy analysis also allows an estim ate of foldability. By applying the method to sequences with 27 and 12 5 residues, we show that optimal folding occurs near the folding trans ition temperature and at either zero or small negative average interac tion energy. We find ourselves able to fold only 125-mers that have si gnificant short-range native contacts. Conclusions: A free energy anal ysis during unfolding is a useful tool for the study of foldability an d should be applicable to a variety of folding models. In this way we are able to fold some 125-mer designed sequences and our results confi rm the finding that short-range contacts contribute to foldability.