No abstract

A mechanism is proposed for the folding of protein chains. On the basis of short-range interactions, certain aminoacid sequences have a high propensity to be, say, a-helical. However, these short helical (or other ordered) regions can be stabilized only by long-range interactions arising from the proximity of two such ordered regions. These regions are brought near each other by the directing influence of certain other aminoacid sequences that have a high probability of forming,8-bends or variants thereof, also on the basis of short-range interactions. An analysis is made of the tendency of various amino acids to occur in ,-bends, and it is possible to predict the regions of a chain in which a (-bend will occur with a high degree of reliability.In this series of papers, we will present a specific mechanism for the folding of a polypeptide chain into the native structure of a globular protein. In this presentation, we will attempt to demonstrate that specific backbone conformations such as the right-handed a-helix (aR), the (3-structure, and the (-bend, found to varying extents in the native structures of most globular proteins, are not only essential for the structural integrity of the protein but also are remnants of structures that play a key role in the folding process.In this initial paper, we give a general description of the proposed mechanism, as well as some illustrative correlations between the aminoacid sequence and native structure of a protein that provide support for this mechanism. In subsequent papers in this series, we will discuss the energetics of the folding process. PROPOSED MECHANISMThe protein molecule, under sufficiently denaturing conditions (or even, perhaps, directly after synthesis), behaves essentially as a random coil. Since the number of states accessible to the polypeptide chain in the random-coil condition is immense, it is reasonable to assume that (a) the folding of the chain into its most stable (native) conformation is not the result of a random event, and (b) a specific pathway exists for the folding process.It was previously suggested (1) that one of the initial steps (which might be considered a nucleation step) during the folding process is the fortuitous meeting of two distant sections of the protein chain to form a stabilized pair of ahelices (or, for that matter, any other ordered structure), around which the rest of the polypeptide chain could fold. This idea developed from the demonstration (1) that, for most proteins, those portions of the chain that have a high helical probability in the denatured condition are found to be in the aR conformation in the native structure. Further, it was shown (2) that, for the cytochrome c proteins of 27 species, the regions of high helical probability were, for the most part, conserved from species to species; this result is consistent not only with the proposed invariance of the native conformation of these proteins (3), but also with our proposal that these regions of high helical probability aid in directing the folding t...

The conformational space accessible to the N‐acetyl N′‐methyl amides of the 20 naturally occurring amino acids has been explored extensively with the aid of empirical energy functions, and many minima have been located. The statistical weights for all minima with energy ≤ 3 kcal above the lowest for each residue have been calculated. In numerous cases, the conformation of lowest energy does not possess the highest statistical weight, thereby emphasizing the importance of considering the conformational librations when comparing theoretical and experimental results. The calculated minimum‐energy conformations, as well as those of highest statistical weight, are for the most part in good agreement with experimental results from studies of these compounds in solution and in the crystalline state.

Interactions of aluminum with deoxyribonucleic acid (DNA) have been studied by thermal denaturation, circular dichroism, and fluorescent dye binding; a pH- and concentration-dependent alteration in the interaction of aluminum with DNA was observed. Three distinguishable complexes are produced when DNA is denaturated at pH 5.0-7.5 and in aluminum to DNA mole ratios of 0-0.7. Complex I appears at neutral pH and stabilizes a portion of DNA. Complex II is observed at acidic pH, destabilizes a fraction of the DNA double-helical molecule, and produces intrastrand cross-links. Complex III occurs at all pHs, is maximal at intermediate pH values, and is characterized by a noncooperative melting profile and cross-linking at low pH (less than 6.0). The DNA in complexes II and III can be renatured by treatment with either ethylenediaminetetraacetic acid (EDTA) or a high concentration of sodium chloride. The properties of complexes I and II are consistent with what could be expected for DNA complexes of Al(OH)2+ and Al3+, respectively. Complex III has intermediate properties that are consistent with a structure in which both ions bind the DNA simultaneously. The characteristics of complex III depend on the ratio of Al3+/Al(OH)2+ in solution. Aluminum-DNA complexes differ from other metal-DNA complexes in that melting profiles under many conditions are biphasic. Apparently more than one form of DNA can exist at any time in the presence of aluminum. The different DNA-aluminum complexes, which arise from the multiple species of aluminum in aqueous solution, lead to a variety of reactions with DNA.