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C Chothia

Publications and source records attributed to C Chothia.

At least 109 records · Page 6Linked to original sources
PubMed1982

Orthogonal packing of beta-pleated sheets in proteins.

Two classes of beta-sheet to beta-sheet packing can be distinguished in globular proteins. Both classes have beta sheets with the usual right-handed twist packed face to face. In orthogonal beta-sheet packings, the strand directions of the different beta sheets are 90 degrees to each other. Twisted beta sheets in this orientation have anticomplementary surfaces: one pair of diagonally opposite corners in the beta sheets is very close, and the other pairs of corners splay apart. At the close corners, the beta sheets are usually covalently connected: a strand that is part of one beta sheet turns through a right-handed bend to become part of the second beta sheet. The bend may occur at a beta bulge, or over a stretch of residues with a characteristic conformation, forming what we call a beta bend. Contacts between the beta sheets occur along the diagonal joining the close corners. They improve about one-fourth of the beta-sheet residues, and two-thirds of them are Val, Ile, or Leu. Elsewhere, the space between the beta sheets is filled by side chains from other parts of the protein, often alpha helices placed at the splayed corners. Examples of orthogonal beta-sheet packing are found in alcohol dehydrogenase, the acid proteases, the trypsin family, papain, staphylococcal nuclease, and thermolysin. In aligned beta-sheet packings, the angle between the strand directions of the packed beta sheets is approximately -30 degrees. In this orientation, the twisted beta-sheet surfaces are complementary. The principles governing this class of beta-sheet packings have been described previously. Here we discuss the difference and similarities of the aligned and orthogonal packing classes.

Alcohol Oxidoreductases↗
PubMed1980

Solvent accessibility, protein surfaces, and protein folding.

Studies of the native structures of proteins, together with measurements of the thermodynamic properties of the transition between unfolded and native states, have defined the major components of the forces that stabilize native protein structures. However, the nature of the intermediates in the folding process remains largely hypothetical. It is a fairly widespread and not implausible assumption that the intermediates in the folding of a monomeric protein contain the same kinds of secondary and tertiary structures that appear in the native conformation, and that, although unstable, their lifetimes are prolonged by forces similar to those that stabilize the native structure. We wished to examine what happens if, during the folding of a monomeric protein, regions of secondary structure come together to form an intermediate of reduced instability. We applied calculations of accessible surface area (a measure of hydrophobic stabilization) and parameterized nonbonded energy calculations (measuring the strengths of van der Waals forces) to identify the kinds of stabilizing interactions that might be available to such an intermediate. First, we analyzed the total buried surface area of two types of proteins into contributions from formation of secondary structure alone, interaction of pairs of secondary-structural elements, the formation of the structure alone, interaction of pairs of secondary-structural elements, the formation of the complete secondary structure without the turns, and the complete native structure. The formation of secondary structure alone, without tertiary-structural interactions, buries roughly half the surface that the complete structure does. We then analyzed in more detail the approach of two alpha-helices to form a complex, as an illustrative example of the nature of the interaction between compact structural units which remain fairly rigid during their interaction. Many features of the results are not limited to the interaction of alpha-helices. (The results therefore neither confirm nor refute the hypothesis that alpha-helices are intermediates in the folding proteins). We find that the first forces to be felt upon approach arise from solvent conditions on the relative position and orientation of the two helices as does the close packing which optimizes the van der Waals interactions at shorter distances apart. Therefore there appears to be a range of distances in which hydrophobic interactions could create a nonspecific complex between two helices in which the side chains might have sufficient time to seek the proper interdigitation observed in the native structure, where the two helices are in intimate contact. Indeed, we find that only in the final stages of approach is the native geometry the most stable; in the region in which solvent-exclusion forces predominate, the conformation with helix axes parallel is more stable than the native conformation, in the cases we examined...

Animals↗
PubMed1978

Role of hydrophobicity in the binding of coenzymes. Appendix. Translational and rotational contribution to the free energy of dissociation.

We calculate the loss of surface area accessible to solvent associated with coenzyme binding in Clostridium flavodoxin, in dogfish lactate dehydrogenase, and in lobster glyceraldehyde-3-phosphate dehydrogenase. The coenzymes are nearly buried in the complexes and lose on the order of 600 A2, while the proteins lose a similar amount of accessible surface area. Some of the loss can be attributed to conformation changes in the protein, at least in the case of lactate dehydrogenase, where we show that the apoenzyme has a larger accessible surface area than the holoenzyme. Using known correlations with the hydrophobic contribution to the free energy, we demonstrate that hydrophobicity is the major source of stabilization free energy in FMN binding to flavodoxin and in NAD binding to the two dehydrogenases: it contributes 25 to 30 kcal/mol to the free energy of dissociation, more than required in order to compensate for the loss of six degrees of translational/rotational freedom by the coenzyme.

Animals↗
PubMed1977

Structure of proteins: packing of alpha-helices and pleated sheets.

Simple models are presented that describe the rules for almost all the packing that occurs between and among alpha-helices and pleated sheets. These packing rules, together with the primary and secondary structures, are the major determinants of the three-dimensional structure of proteins.

Models, Chemical↗
PubMed1976

Structural patterns in globular proteins.

A simple diagrammatic representation has been used to show the arrangement of alpha helices and beta sheets in 31 globular proteins, which are classified into four clearly separated classes. The observed arrangements are significantly non-random in that pieces of secondary structure adjacent in sequence along the polypeptide chain are also often in contact in three dimensions.

Models, Structural↗
PubMed1976

Role of subunit interfaces in the allosteric mechanism of hemoglobin.

We calculate the surface area buried in subunit interfaces of human deoxyhemoglobin and of horse methemoglobin. A larger surface area is buried in deoxy- than in methemoglobin as a result of tertiary and quaternary structure changes. In both molecules the dimer-dimer interface is closepacked. This implies that hydrophobicity stabilizes the deoxystructure, the free energy spent in keeping the subunits in a low-affinity conformation being compensated by hydrophobic free energy due to the smaller surface area accessible to solvent.

Allosteric Regulation↗
PubMed1975

Principles of protein-protein recognition.

The formation of the protein-protein interface by the insulin dimer, the trypsin-PTI complex and the alphabeta oxyhaemoglobin dimer removes 1,130-1,720 A2 of accessible surface from contact with water. The residues forming the interface are close packed: each occupies the same volume as it does in crystals of amino acids. These results indicate that hydrophobicity is the major factor stabilising protein-protein association, while complementarily plays a selective role in deciding which proteins may associate.

Animals↗