Is the hydrophobic core a universal structural element in proteins?

Abstract

The hydrophobic core, when subjected to analysis based on the fuzzy oil drop model, appears to be a universal structural component of proteins irrespective of their secondary, supersecondary, and tertiary conformations. A study has been performed on a set of nonhomologous proteins representing a variety of CATH categories. The presence of a well-ordered hydrophobic core has been confirmed in each case, regardless of the protein's biological function, chain length or source organism. In light of fuzzy oil drop (FOD) analysis, various supersecondary forms seem to share a common structural factor in the form of a hydrophobic core, emerging either as part of the whole protein or a specific domain. The variable status of individual folds with respect to the FOD model reflects their propensity for conformational changes, frequently associated with biological function. Such flexibility is expressed as variable stability of the hydrophobic core, along with specific encoding of potential conformational changes which depend on the properties of helices and β-folds.

Keywords: Hydrophobic core; Hydrophobicity; Protein folding.

Fig. 1

Graphical representation of fuzzy oil drop model hydrophobicity distributions obtained for a hypothetical protein reduced to a single dimension for simplicity. A is the theorized Gaussian distribution (blue) while chart C corresponds to the uniform distribution (green). Actually observed (red) hydrophobicity density distribution in the target protein B, while its corresponding value of RD (relative distance) in D is marked on the horizontal axis with a red diamond. According to the fuzzy oil drop model this protein does not contain a well-defined hydrophobic core, because its RD value, equal to 0.619, is above the 0.5 threshold (or, generally, closer to R than to T)

Fig. 2

3D representation of 1A5Z-D1 (A) and 1FW8-D2 (B). Fragments marked in red diverge from the theoretical model (RD > 0.5)

Fig. 3

Hydrophobicity density distribution profiles (T – theoretical – green; O – observed – red) in 1A5Z-D1 and 1FW8-D2 (charts A and B respectively). Gray areas mark fragments where RD > 0.5

Fig. 4

3D structures of 1B4L and 1CON, with fragments exhibiting high discordance (RD > 0.5) marked in red (Table 3). Spheres correspond to ion binding residues

Fig. 5

Hydrophobicity distribution charts for 1B4L (A) and 1CON (B). Gray bands mark divergent fragments

Fig. 6

Hydrophobicity distribution profiles (theoretical – blue and observed – red) for 1AMK (A) with indication of eliminated fragments, along with 4DRS (B) with indication of eliminated fragments (blue) and the placement of ligand binding residues (green)

Fig. 7

3D presentation of 1AMK (A – catalytic residues visualized with CPK; fragments exhibiting RD > 0.5 marked in red) and 4DRS (B – ligand-binding residues colored with CPK; eliminated residues colored pink; fragments exhibiting RD > 0.5 marked in red)

Fig. 8

3D presentation of 1RBP (A), 1PNG (B), and 1TIM (C) with discordant fragments marked in red. Residues plotted with CPK represent catalytic residues

Fig. 9

3D representation of 7FAB immunoglobulin domains: VL (A), CL (B), VH (C), and CH (D). Fragments marked in red satisfy RD > 0.5

Fig. 10

N-terminal domain of dogfish lactate dehydrogenase (6LDH) – theoretical (T – blue) and observed (O – red) distributions indicating the presence of a prominent hydrophobic core

Fig. 11

3D representation of the N-terminal domain (20–162) of 6LDH. Fragments marked in red exhibit RD > 0.5 while the fragment marked in green corresponds to the right-handed helical fold causing β-strand flanking

Fig. 12

3D representation of cytochromes with fragments exhibiting RD > 0.5 marked in red: 4 J20 (A), 155C (B), 256B (C), 1JD2 (D), 2C2C (E), and 5CYT (F). Pink fragments are involved in interaction with the ligand (heme)