Expedience of Protein Folding Modeling during Progressive Elongation of Polypeptide Chain

Abstract

The problem of protein folding, i.e. how does a polypeptide chain fold to native protein following its synthesis on the ribosome, is recognized as a major unsolved problem of biology at molecular level. To solve the problem experimental studies of denaturation and renaturation of native proteins and a variety of theoretical-computational simulations of full-length polypeptide chains have usually been used as relevant in vitro models. However, at present these conventional approaches evidently seem to be hypothetical and have been hardly found. Nevertheless, there are a lot of convincing evidences that proteins fold progressively during the residue-by-residue elongation on the ribosome from the N- to the C-terminus. On this basis, therefore, simulations of the folding and formation of the native spatial structure of the proteins will be expedient. These points are briefly highlighted in the current minireview. The problem of protein folding is formulated simply as either how a protein molecule acquires the native spatial structure following its synthesis on the ribosome, or how does the primary amino acid sequence determine protein native tertiary structure, or what is the mechanism of folding the proteins. To solve the problem the traditional in vitro approaches present protein folding as a spontaneous process during which the formation of the native spatial structure of proteins occurs from an unfolded random coil state both in vivo and in vitro (1-5). For example, unfolded full-length polypeptide chains are usually considered as the objects under study to explore the mechanism of folding the proteins following their synthesis on the ribosome. The consideration has been developed in the 1970's on the basis of the results of the classical experiments on denaturation and renaturation of the small single-domain proteins (6), herewith of special importance were the results of the experiments on bovine pancreatic ribonuclease (7-10). Such experiments demons- trated: firstly, proteins unfold and adopt a random coil state under strongly denaturing conditions with no residual ordered structure being present, and secondly, some of the denatured proteins restore their initial native state relatively quickly and spontaneously after removal of denaturation (6- 10). At present, it is evidently clear that neither denatured nor newly synthesized protein is randomly coiled. A slight per- ceptible indication of residual regular structures was detected in some proteins under strongly denaturing conditions yet in the early classical denaturation experiments (6, 11, 12).