Origins of structure in globular proteins.

Abstract

The principal forces of protein foldinghydrophobicity and conformational entropy-are nonspecific.A long-standing puzzle has, therefore, been: What forces drive the formation of the specific internal architectures in globular proteins? We find that any self-avoiding flexible polymer molecule will develop large amounts of secondary structure, helices and parallel and antiparallel sheets, as it is driven to increasing compactness by any force of attraction among the chain monomers. Thus structure formation arises from the severity of steric constraints in compact polymers. This steric principle of organization can account for why short helices are stable in globular proteins, why there are parallel and antiparallel sheets in proteins, and why weakly unfolded proteins have some secondary structure. On this basis, it should be possible to construct copolymers, not necessarily using amino acids, that can collapse to maximum compactness in incompatible solvents and that should then have structural organization resembling that of proteins.What force causes the internal architectures in globular proteins? Although the dominant force of folding is the hydrophobic interaction (1) (ii) The most stable helices (21,22) are typically longer than 15 residues and are not completely helical; in contrast in globular proteins, the average helix length is 12 residues, the most common helix length is less than 6 residues (18-20), and these are 100% helical up to nearly the denaturation temperature of the protein.(iii) "Local" sequence information has been insufficient to predict protein structures (23-26). What then is the origin of the regular and irregular conformations that comprise globular proteins?Lattice Approach

Folding the Main Chain of Small Proteins with the Genetic Algorithm

“…The effectiveness of such simple forces in eliciting the main-chain topology is also consistent with the molten globule (Kuwajima, 1989), which IS characterized by secondary structure formation and association yet lacks specific side-chain interactions, thus implying that the backbone fold is achieved by relatively non-specific interactions of the type found in our fitness function. Our work also represents a nice extension of the results of Chan & Dill (1990, 1993 and Skolnick & Kolinski (1990) , who use Monte Carlo grid-bound simulations in two and three dimensions and who also emphasize the importance of simple forces in achieving the proper fold . Our work is nonetheless free from fold biases due to particular grid topologies (Gregoret & Cohen, 1991).…”

Side‐chain entropy and packing in proteins

“…Even if all side chains have uniform size and shape, as in the SCM, they contribute to specifying a native fold by reducing the number of viable compact conformations. The drive to compact states reduces the number of conformations by many orders of magnitude and in this respect contributes to selecting the native fold from among all possible conformations (Dill, 1985;Chan & Dill, 1990a). Figures 3, 4, 5 , and 6 show that the addition of uniform side chains to a linear chain model further selects from among the possible compact states those configurations that can also accommodate the side chains.…”

“…Incorporation of specific monomer sequences and sticking energies in the 2D LCM models leads to the following properties of proteins: (I) For a substantial fraction of sequences, small changes in conditions near a point of marginal stability lead to a sharp folding transition, from a large ensemble of denatured conformations to a small number of highly compact conformations with a hydrophobic core (Lau & Dill, 1989, 1990Chan & Dill, 1991). (2) The compact configurations have length distributions of helices and parallel and antiparallel sheets similar to the protein structures in the Brookhaven Protein Data Bank (PDB) (Chan & Dill, 1990a). (3) The following protein mutational properties are found: (a) The surface monomers are more neutral to mutation than core monomers.…”

Prediction of protein conformation on the basis of a search for compact structures: Test on avian pancreatic polypeptide

“…Application of this procedure to the 36-residue avian pancreatic polypeptide led to a structure that resembled the one determined by X-ray crystallography; it had an a-helix starting at residue 13, with the N-terminal portion of the chain in an extended conformation packed against the a-helix. Similar structures with slightly higher energies, but looser packing, were also obtained.Keywords: compact conformations; conversion from a united-residue representation to an all-atom chain; hydrophobic-residue packing; Monte Carlo methods; multiple-minima problem; potential of mean force; protein folding; united-residue representation of a polypeptide chain In our continuing effort to surmount the multiple-minima problem (Scheraga, 1989;Kostrowicki & Scheraga, 1992;Olszewski et al, 1992) in computing the structure of a protein, we have developed a procedure that takes advantage of the fact that the protein core tends to consist of tightly packed nonpolar residues, with the polar ones located on the surface (Kauzmann, 1959;Rackovsky & Scheraga, 1977;Richards, 1977;Wertz & Scheraga, 1978;Chan & Dill, 1990;. Such an example of selforganization is reminiscent of early work by Onsager (1949) on the packing of tobacco mosaic virus particles and by Flory (1956) on the packing of rodlike polymers (including a-helices).…”