Conformational entropy proteins

Disulfides. The introduction of disulfide bonds can have various effects on protein stability. In T4 lyso2yme, for example, the incorporation of some disulfides increases thermal stability others reduce stability (47—49). Stabili2ation is thought to result from reduction of the conformational entropy of the unfolded state, whereas in most cases the cause of destabili2ation is the introduction of dihedral angle stress. In natural proteins, placement of a disulfide bond at most positions within the polypeptide chain would result in unacceptable constraint of the a-carbon chain. 

P Koehl, M Delarue. Application of a self-consistent mean field theory to predict protein side-chains conformation and estimate their conformational entropy. J Mol Biol 239 249-275, 1994. 

If peptide residues are converted to peptoid residues, the conformational heterogeneity of the polymer backbone is likely to increase due to cis/trans isomerization at amide bonds. This will lead to an enhanced loss of conformational entropy upon peptoid/protein association, which could adversely affect binding thermodynamics. A potential solution is the judicious placement of bulky peptoid side chains that constrain backbone dihedral angles. 

A change in the environment of a protein molecule, e.g. adsorption from aqueous solution onto a sorbent surface, may lead to a partial breakdown of its ordered structure, resulting in an increase of conformational entropy. This is a fundamental difference between protein adsorption and the adsorption of flexible polymers, for which attachment to a surface implies a loss of conformational entropy. 

Based on these contributions (a-d), we may arrive at the predictive scheme presented in Table 1. Because of the relatively large contribution from dehydration, essentially all proteins adsorb from an aqueous environment on apolar surfaces, even under electrostatically adverse conditions. With respect to polar surfaces, distinction may be made between proteins having a strong internal coherence ( hard proteins) and those having a weak internal coherence ( soft proteins). The hard proteins adsorb at polar surfaces only if they are electrically attracted, whereas the structural rearrangements (i.e., reductions in ordered structure) in the soft proteins lead to a sufficiently large increase in conformational entropy to make them adsorb at a polar, electrostatically repelling surface. 

The influence of adsorption on the structure of a -chymotrypsin is shown in Fig. 10, where the circular dichroism (CD) spectrum of the protein in solution is compared with that of the protein adsorbed on Teflon and silica. Because of absorbance in the far UV by the aromatic styrene, it is impossible to obtain reliable CD spectra of proteins adsorbed on PS and PS- (EO)8. The CD spectrum of a protein reflects its composition of secondary structural elements (a -helices, / -sheets). The spectrum of dissolved a-chymotrypsin is indicative of a low content of or-helices and a high content of //-sheets. After adsorption at the silica surface, the CD spectrum is shifted, but the shift is much more pronounced when the protein was adsorbed at the Teflon surface. The shifts are in opposite directions for the hydrophobic and hydrophilic surfaces, respectively. The spectrum of the protein on the hydrophilic surface of silica indicates a decrease in ordered secondary structure, i.e., the polypeptide chain in the protein has an increased random structure and, hence, a larger conformational entropy. Adsorption on the hydrophobic Teflon surface induces the formation of ordered structural elements, notably an increase in the content of O -helices (cfi, the discussion in Sect. 3.1.4). 

In addition to enthalpic contributions, the entropy effects accompanying protein-metal ion interactions are substantial. These effects manifest themselves in the desolvation of the metal ion and its binding site. However, as the metal ion binds to a protein, the entropy gain of solvent release may be offset to some degree by the reduction of the conformational entropy of the polypeptide chain as it becomes more firmly bound... 

The native state of a protein has many of its hydrophobic side chains shielded from water because they are packed in hydrophobic cores. Conversely, the denatured state has many of its hydrophobic side chains exposed to solvent. The water molecules stack around these in icebergs as they maximize their hydrogen bonds with one another (Chapter 11). This lowers the entropy of water, because the individual molecules have less freedom of movement, and lowers the enthalpy because more hydrogen bonds are made.2 Similarly, the hydrogen bond donors and acceptors in the polypeptide backbone of the denatured protein are largely exposed to solvent and tie down more water molecules.3 These water molecules are released as the protein folds, and the gain in entropy of water compensates considerably for the loss of conformational entropy. 

Disulfide bridges are thought to stabilize proteins primarily by destabilizing the denatured state by reducing its conformational entropy. They can contribute up to 4 kcal/mol (17 kJ/mol) per disulfide bridge to the stability, and similar values... 

Theory suggests that the most probable loops in proteins contain 10 residues.59 Shorter loops become stiff and longer ones lose more conformational entropy— recall from Chapter 17 that AiSconfig — a — (3/2)/ Inn. Indeed, the kinetics of formation of longer loops does fall off as exp(— 3/2) In n), = n (3/2) where n is the number of residues in the loop.60 A 50-residue loop in cytochrome c closes with ty2 of 40 fJL, implying a maximum closing rate of 106 s-1.7... 

Protein conformational changes contribute positively both to the enthalpy and entropy of adsorption. Such contributions are pH-dependent. 

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