Polypeptide secondary structural propensities

Pawar et al. were able to show that the generic factors affecting amyloidosis are hy-drophobicity, secondary structure propensity and charge and used these to create intrinsic Z-scores for aggregation of any polypeptide, enabling calculation and comparisons between different polypeptide sequences (Pawar et al. 2005). 

In this section we discuss mainly three types of potential terms computed from statistical analyses (Figure 2) (a) the residue-residue interaction potentials considered to represent local and nonlocal interactions between residues along the polypeptide chain (b) the local backbone potential, representing local interactions such as those associated with secondary structure propensities and (c) the profile-like potentials, considered to represent the interactions of individual residues with their three-dimensional environment. In contrast to molecular mechanics force fields, which have converged to a small number of functional forms and parameter sets, the implementations of these various potentials remain rather diverse. In the following we illustrate these implementations with some specific examples, and use these as the basis to review the approaches taken by various authors. 

In the latter implementation, the residue interaction potentials measure the propensities P l °j (dij) of amino acid pairs at positions / and j along the sequence to be separated by a given spatial distance d. Residue pairs are partitioned according to the number of positions / — j that separates them along the polypeptide sequence. In order to try and distinguish between local contributions associated with secondary structure propensities and nonlocal tertiary interactions, pairs of consecutive residues are not considered, because their spatial distance is roughly constant. For pairs separated by 2-8 sequence positions (1 < f — j < 8), probabilities are computed for each separation individually, yielding seven... 

The biological function of peptides and proteins depends on their native conformation. The side-chain functionalities of the a-amino acids that comprise peptides and proteins have profound effects on their properties. These functionalities reside in the 20 naturally occurring a-amino acids, which have different propensities for formation of the three major secondary structural conformations. 1 In addition to these naturally occurring a-amino acids whose primary structure enables the polypeptide to fold into a predictable secondary and tertiary structure, the incorporation of unnatural amino acids has opened important areas of research. 

How does the amino acid sequence of a protein specify its three-dimensional structure How does an unfolded polypeptide chain acquire the form of the native protein These fundamental questions in biochemistry can be approached by first asking a simpler one What determines whether a particular sequence in a protein forms an a helix, a (3 strand, or a turn One source of insight is to examine the frequency of occurrence of particular amino acid residues in these secondary structures (Table 2.3). Residues such as alanine, glutamate, and leucine tend to be present in a helices, whereas valine and isoleucine tend to be present in (3 strands. Glycine, asparagine, and proline have a propensity for being present in turns. 

Despite this low thermodynamic stability the permanent existence of a single secondary amide peptide bond in cis conformation per 1000 amino acid residues is the minimal population that has to be considered for unfolded polypeptide chains. This cis peptide bond fluctuates across the polypeptide chain in relation to the sequence-specific propensity of a secondary amide peptide bond to adopt the cis conformation. As could be found in folded proteins, nonprolyl cis peptides are frequently located in the fS-region of a q>/y/ plot [22]. It was hypothesized that cis peptide bonds represent high-energy structures able to store potential energy for increasing chemical reactivity [23]. Interconversion rates for the reversible CTI of secondary amide peptide bonds typically lead to half times of about 1 s for dipeptides, which decreases about 4-fold when the peptide bond is positioned in the middle of a longer peptide chain. 

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