Hydrophobic-polar model, protein folding

The van der Waals model of monomeric insulin (1) once again shows the wedge-shaped tertiary structure formed by the two chains together. In the second model (3, bottom), the side chains of polar amino acids are shown in blue, while apolar residues are yellow or pink. This model emphasizes the importance of the hydrophobic effect for protein folding (see p. 74). In insulin as well, most hydrophobic side chains are located on the inside of the molecule, while the hydrophilic residues are located on the surface. Apparently in contradiction to this rule, several apolar side chains (pink) are found on the surface. However, all of these residues are involved in hydrophobic interactions that stabilize the dimeric and hexameric forms of insulin. 

This chapter aims to summarize our efforts to investigate the effects of fluorinated amino acid substitutes on the interactions with natural protein environments. In addition to a rather specific example concerning the interactions of small peptides with a proteolytic enzyme, we present a simple polypeptide model that aids for a systematic investigation of the interaction pattern of amino acids that differ in side chain length as well as fluorine content within both a hydrophobic and hydrophilic protein environment. Amino acid side chain fluoiination highly affects polypeptide folding due to steric effects, polarization, and fluorous interactions. 

A large number of macromolecules possess a pronounced amphiphilicity in every repeat unit. Typical examples are synthetic polymers like poly(l-vinylimidazole), poly(JV-isopropylacrylamide), poly(2-ethyl acrylic acid), poly(styrene sulfonate), poly(4-vinylpyridine), methylcellulose, etc. Some of them are shown in Fig. 23. In each repeat unit of such polymers there are hydrophilic (polar) and hydrophobic (nonpolar) atomic groups, which have different affinity to water or other polar solvents. Also, many of the important biopolymers (proteins, polysaccharides, phospholipids) are typical amphiphiles. Moreover, among the synthetic polymers, polyamphiphiles are very close to biological macromolecules in nature and behavior. In principle, they may provide useful analogs of proteins and are important for modeling some fundamental properties and sophisticated functions of biopolymers such as protein folding and enzymatic activity. 

The findings gained with the model system show that two contrary effects characterize the interactions of fluorinated amino acids within the hydrophobic core spatial demand and hydrophobicity on one side, and fluorine-induced polarity on the other. While the increase in hydrophobic surface area upon fluorination may be favorable for hydrophobic interactions, fluorine s inductive effect appears to interfere with the formation of an intact hydrophobic core. In addition, the investigations of fluoroalkyl side-chains in the charged domain as well as the analysis of fluorine s effect on replicase activity indicate that contacts between fluorinated residues may also have an impact on peptide and protein folding. 

The interactions between the amino acids and the solvent (electrostatic, hydrophilic, hydrophobic, S-S) determine the globular conformation. We can give some naive picture of the folded state in terms of a liquid-hydrocarbon model where the hydrophobic core stabilizes globular proteins. The hydrophilic (polar and charged) amino acids are exposed to the solvent and the hydrophobic (polar) amino acids are less exposed to the solvent and buried in the interior of the protein. 

Since lattice models suffer from undesired effects of the underlying lattice symmetries, simple hydrophobic-polar off-lattice models were introduced. One such model is the AB model, where, for historical reasons, A symbolizes hydrophobic and B polar regions of the protein, whose conformations are modeled by polymer chains in continuum space governed by effective bending energy and van der Waals interactions [14]. These models allow for the analysis of different mutated sequences with respect to their folding... 

The simplest model for a quahtative description of protein folding is the lattice hydrophobic jolar (HP) model [12]. In this model, the continuous conformational space is reduced to discrete regular lattices and conformations of proteins are modeled as selfavoiding walks restricted to the lattice. Assuming that the hydrophobic interaction is the most essential force toward the native fold, sequences of HP proteins consist of only two types of monomers (or classes of amino acids) Amino acids with high hydrophobicity are treated as hydrophobic monomers (//), while the class of polar (or hydrophihc) residues is... 

These phenomena can also be expected to occur in the aggregation process of polymers. To this end, we will now investigate the aggregation behavior of a mesoscopic hydrophobic-polar heteropolymer model for aggregation [254, 255], which is based on the simple AB model [14] that we have already discussed in the context of tertiary folding behavior of proteins from a generic, coarse-grained point of view. 

Figure 5.1. Modelled structure of a 42-residue peptide folded into a helix-loop-helix motif and dimerized to form a four-helix bundle protein. Helices are amphiphilic with a hydrophobic and a polar face. Due to the robustness and ease of synthesis this has become a popular motif in de novo protein design.

Lau and Dill have also investigated the statistical mechanics of folding for simplified protein models on two-dimensional square lattices. They explored both conformational space (the set of all possible conformations) and sequence space (the set of all possible sequences) and concluded that many sequences have stable, compact, native-like structures. Another conclusion of these studies was that sequences tended to form a single, unique structure, even with only two types of residues (hydrophobic and polar). This tendency increased with chain length. Moreover, one or two mutations in these sequences did not greatly destabilize most folded states. 

To clarify the relevance of non-native intermediates in the folding of proteins dictated by the formation of disulfide bonds Camacho and Thirumalai [45] used lattice models. While these models are merely caricatures of proteins, they contain the specific effects that can be studied in microscopic detail. We used a two-dimensional lattice sequence consisting of hydrophobic (H), polar (P), and Cys (C) residues. If two C beads are near neighbors on the lattice, they can form a S-S bond with an associated energy gain of —with > 0. Thus, topological specificity is required for native S-S bond formation in this model. We have studied the folding kinetics of this model, which is perhaps the simplest model that can probe the characteristics of native and non-native disulfide bonded intermediates. 

FIGURE 8.4 Intrinsically disordered proteins (IDPs). The balance between polar and apolar residues in a protein is a key parameter that controls the formation of a hydrophobic core in water. Proteins with too much polar versus apolar residues will not fold through an entropicaUy driven mechanism and will instead adopt a myriad of conformations in water (4 possible conformers of the same protein are shown from the top of the cartoon). These proteins, referred to as "intrinsically disordered proteins" (IDPs), lack a precise 3D structure in water. IDPs have a high level of conformational plasticity and they can adapt their conformation to various molecular partners, which can be either a protein or a membrane. In this example, the protein is acidic (red surface in the lower model). The sequence of the protein is shown at the bottom of the illustration (apolar residues in black, acidic in red, and polar but not acidic in green). 

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