We have compared the behavior in solution of the synthetic polynucleotide poly(dG-m5dC)poly(dG-m5dC) with that of the unmethylated polynucleotide poly(dG-dC)poly(dGdC). In solutions containing high concentrations of salt, poly(dGdC)-poly(dG-dC) is known to exhibit altered circular dichroic and absorption spectra correlated with formation of a left-handed Z DNA structure. poly(dG-m5dC) behaves similarly, but the spectral transition from the B to the Z form occurs at much lower salt concentrations, close to usual physiological conditions. Divalent and polyvalent ions are particularly effective: The B-Z transition of poly(dG-m5dC) (dG-m5dC) can be induced at a Mg2e concentration three orders of magnitude lower than that required for the unmethylated polymer. We have also studied mixed copolymers containing both dC and m5dC. Our results suggest that the sequence m5dC-dG, which occurs in eukaryotic DNA, can have a disproportionately large effect on the B-Z transition.transcriptional activity of the gene (7). For these reasons, we wished to compare the properties of the methylated C-G synthetic polymer with the unmethylated compound.We have found that, as judged by circular dichroism and ultraviolet absorption, poly(dG-m5dC)poly(dG-m5dC) also undergoes a transition from the B to the Z form, but at much lower salt concentrations, so that the Z form is stable under typical physiological conditions. Furthermore, in mixed alternating copolymers of dG-dC and dG-m5dC, the presence of the latter sequence has a disproportionate effect in lowering the amount of divalent ion required to stabilize the Z form. Our results provide some information about the forces that govern the B-Z transition and suggest that there are circumstances in which the Z form might be observed in vivo.It is now accepted that DNA of appropriate nucleotide sequence is capable of forming left-handed double helical structures with Watson-Crick base pairing, as well as the more familiar righthanded structures. X-ray crystallographic studies of the synthetic oligonucleotide d(CpGpCpGpCpG), demonstrated the left-handed, or Z-DNA, conformation (1). Subsequent studies of the smaller oligonucleotide d(CpGpCpG) suggested that there are at least two related Z conformations (2, 3). Diffraction patterns consistent with the Z form have also been observed (4) with fibers of the high molecular weight alternating copolymer poly(dG-dC)-poly(dG-dC) and with poly(dAdC)poly~dG-dT).The solution properties of poly(dG-dC)-poly(dG-dC) were described and analyzed by Pohl and Jovin some years ago (5). They showed that at high salt concentrations (above 2.5 M NaCl or 0.7 M MgCl2) the polynucleotide is converted to a new form by a cooperative, intramolecular process. This new form displays a circular dichroic spectrum that is inverted compared to that of the B form, and an ultraviolet absorption spectrum with increased molar extinction compared to the B form in the range 280-300 nm. The recent x-ray diffraction results, as well as nuclear magnetic resonance studies in sol...

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A globular protein adopts its native threedimensional structure spontaneously under physiological conditions. This structure is specified by a stereochemical code embedded within the amino acid sequence of that protein.Elucidation of this code is a major, unsolved challenge, known as the protein-folding problem. A critical aspect of the code is thought to involve molecular packing. Globular proteins have high packing densities, a consequence of the fact that residue side chains within the molecular interior fit together with an exquisite complementarity, like pieces of a three-dimensional jigsaw puzzle [Richards, F. M. (19T71)hAnnu. Rev. Biophys. Bioeng. 6, 151]. Such packing interactions are widely viewed as the principal determinant of the native structure. To test this view, we analyzed proteins of known structure for the presence of preferred interactions, reasoning that if side-chain complementarity is an important source of structural specificity, then sets of residues that interact favorably should be apparent. Our analysis leads to the surprising conclusion that high packing densities-so characteristic of globular proteins-are readily attainable among clusters of the naturally occurring hydrophobic amino acid residues. It is anticipated that this realization will simplify approaches to the protein-folding problem.It is well-known that a protein molecule will adopt its native three-dimensional structure spontaneously under normal physiological conditions (1). The transition to the native state from -a denatured state is called protein folding. Despite intense research, a generalized mechanistic understanding of the folding transition remains obscure. This important question is called the protein-folding problem.A key question-perhaps the key question-is the extent to which protein conformation is determined by packing interactions within the hydrophobic core. This question has its origins in the seminal work of Kauzmann (2), who used model compounds to argue that the burial of hydrophobic groups serves as a primary source of stabilization energy in folded proteins. Later, Richards showed that these buried groups are as well packed, on average, as crystals of small organic molecules, with packing densities more reminiscent of solids than of oil (3, 4). The inside of a typical protein contains side chains that fit together with a striking complementarity, like pieces of a three-dimensional jigsaw puzzle.The high packing densities seen in globular proteins are an experimental fact (3-6). This fact has been interpreted to mean that protein conformation is linked tightly to internal packing. According to this interpretation, for example, lysozyme does not have the same folded conformation as ribonuclease, although both proteins have approximately the same size and composition, because the lysozyme sequence cannot achieve efficient internal packing when organized into a ribonuclease fold. Such an interpretation of packing is consistent with classical studies of protein evolution, where the most conser...

A search of sequence information in the GenBank files shows that tracts of 15-30 contiguous purines are greatly overrepresented in all eukaryotic species examined, ranging from yeast to human. Such an overabundance does not occur in prokaryotic sequences. The large increase in the number of oligopurine tracts cannot be explained as a simple consequence of base composition, nearest-neighbor frequencies, or the occurrence of an overabundance of oligoadenosine tracts. Oligopurine sequences have previously been shown to be versatile structural elements in DNA, capable of occuring in several alternate conformations. Thus the bias toward long oligopurine tracts in eukaryotic DNA may reflect the usefulness of these structurally versatile sequences in cell function.