In general, the results obtained from secondary structure prediction algorithms are often inconsistent with those obtained experimentally. The reason for this disagreement is that the experimentally determined structures have higher free energies (as judged by the currently used "energy rules") than the predicted ones. To overcome this limitation we have developed a new approach which incorporates the frequencies of occurrence of substructures in the growing mRNA chain. This has been accomplished by simulating the folding process of pre-mRNAs. Using this approach we have significantly improved current helical structural prediction for 142 analyzed tRNAs and 16 S rRNA. We have next applied this method to the human alpha-like globins. Comparison of the structures obtained by running the currently used algorithms with those computed by the new method indicates that the final most stable secondary structure contains some infrequently occurring substructures. In addition, some of the frequently recurring substructures are not included in the final structure. Comparison of the simulated folding processes of the human alpha-like globin pre-mRNAs reveals some conserved helices and hairpin loop structures in those frequently recurring substructures. Among these several compensating base changes (transitions and transversions) have been identified.